CN114174276A - Combination therapy to achieve enhanced antimicrobial activity - Google Patents
Combination therapy to achieve enhanced antimicrobial activity Download PDFInfo
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- CN114174276A CN114174276A CN202080053659.7A CN202080053659A CN114174276A CN 114174276 A CN114174276 A CN 114174276A CN 202080053659 A CN202080053659 A CN 202080053659A CN 114174276 A CN114174276 A CN 114174276A
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Abstract
Techniques are provided for enhancing antimicrobial activity of an anti-rheumatic agent by combination therapy. For example, one or more embodiments described herein may relate to a chemical composition comprising a polycarbonate polymer functionalized with guanidinium functional groups. The chemical composition may further comprise an anti-rheumatic agent, and the polycarbonate polymer may enhance the antimicrobial activity of the anti-rheumatic agent.
Description
Background
The present disclosure relates to the use of combination therapy for enhancing the antimicrobial activity of a therapeutic compound, and more particularly to combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent, such as Auranofin (Auranofin).
SUMMARY
The following presents a simplified summary in order to provide a basic understanding of one or more embodiments of the invention. This summary is not intended to identify key or critical elements or to delineate any scope of the particular embodiments or any scope of the claims. Its sole purpose is to present concepts in a simplified form as a prelude to the more detailed description that is presented later. In one or more embodiments described herein, chemical compositions and/or methods are described with respect to one or more combination therapies comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin).
According to one embodiment, a chemical composition is provided. The chemical composition can include a polycarbonate polymer functionalized with a guanidinium functional group. The chemical composition may further comprise an anti-rheumatic agent, and the polycarbonate polymer may enhance the antimicrobial activity of the anti-rheumatic agent.
According to one embodiment, a method is provided. The method may comprise enhancing the antimicrobial activity of the anti-rheumatic agent by combination therapy. The combination therapy can include an anti-rheumatic agent and a polycarbonate polymer functionalized with a guanidinium functionality.
According to one embodiment, a method is provided. The method can include treating the bacterial infection via a combination therapy comprising an anti-rheumatic agent and a polycarbonate polymer functionalized with a guanidinium functional group. Also, the polycarbonate polymer may enhance the antibacterial activity of the antirheumatic agent.
Brief Description of Drawings
The invention will now be described, by way of example only, with reference to preferred embodiments, as illustrated in the following figures:
fig. 1 is a graph illustrating exemplary, non-limiting chemical formulas that may characterize poly (guanidine carbonate) that may be included in combination therapies with one or more anti-rheumatic agents (e.g., auranofin) according to one or more embodiments described herein.
Fig. 2 is a diagram illustrating exemplary non-limiting poly (guanidine carbonate) structures that may be included in combination therapy with one or more anti-rheumatic agents (e.g., auranofin) according to one or more embodiments described herein.
Fig. 3 is a graph illustrating an exemplary, non-limiting translocation mechanism that may be achieved by one or more poly (guanidine carbonate) polymers included in combination therapy with one or more anti-rheumatic agents (e.g., auranofin) according to one or more embodiments described herein.
Fig. 4 is a graph illustrating an exemplary, non-limiting histogram that may depict the efficacy of a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Fig. 5A is a graph illustrating an exemplary, non-limiting graph that may depict the efficacy of a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Fig. 5B is a graph illustrating an exemplary, non-limiting graph that may depict the efficacy of a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Fig. 6A is a graph illustrating an exemplary, non-limiting graph that may depict the efficacy of a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Fig. 6B is a graph illustrating an exemplary, non-limiting graph that may depict the efficacy of a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Fig. 7 is a flow chart illustrating an exemplary, non-limiting method for enhancing antimicrobial activity of one or more anti-rheumatic agents (e.g., auranofin) according to one or more embodiments described herein.
Fig. 8 is a flow chart illustrating an exemplary, non-limiting method for enhancing antimicrobial activity of one or more anti-rheumatic agents (e.g., auranofin) according to one or more embodiments described herein.
Fig. 9 is a flow chart illustrating an exemplary, non-limiting method of treating a bacterial infection via a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Fig. 10 is a flow chart illustrating an exemplary, non-limiting method of treating a bacterial infection via a combination therapy comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent (e.g., auranofin) according to one or more embodiments described herein.
Detailed description of the invention
The following detailed description is merely illustrative and is not intended to limit the embodiments and/or the application or uses of the embodiments. Furthermore, there is no intention to be bound by any expressed or implied information presented in the preceding background or summary or detailed description.
One or more embodiments are now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a more thorough understanding of one or more embodiments. It may be evident, however, that such embodiment(s) may be practiced without these specific details.
There are many challenges to commercializing a new therapeutic chemical compound. For example, commercializing a new therapeutic chemical compound may cost an average of $ 15.2 billion, may take 7-15 years, and/or may have a failure rate of 90%. In addition, regulatory restrictions may be imposed on newly introduced therapeutic chemical compounds. For example, newly introduced antibiotics may have regulatory limitations regarding availability as a prescription and/or agricultural application in order to minimize the development of antibiotic resistance in bacteria.
Various embodiments described herein may relate to repositioning one or more anti-rheumatic agents as an antimicrobial agent (e.g., having antibacterial activity) using a combination therapy with one or more poly (guanidine carbonate) polymers according to one or more embodiments described herein. One or more embodiments may be directed to chemical compositions comprising one or more polycarbonate polymers functionalized with guanidinium functionality and one or more anti-rheumatic agents (e.g., auranofin). The one or more polycarbonate polymers may enhance the antimicrobial activity of the one or more anti-rheumatic agents. For example, the one or more polycarbonate polymers can interact with a target microorganism through a translocation mechanism and precipitate one or more cytoplasmic members. Precipitation of the one or more cytoplasmic members may confer antimicrobial activity to the one or more anti-rheumatic agents that would otherwise be inhibited. For example, the one or more polycarbonate polymers may enable the one or more anti-rheumatic agents to increase the production of reactive oxygen species ("ROS") within microorganisms. Thus, the one or more polycarbonate polymers may enhance the antimicrobial activity of the one or more anti-rheumatic agents and/or reposition the one or more anti-rheumatic agents as broad spectrum antimicrobial agents to treat bacterial infections.
The term "combination therapy" as used herein may refer to the use of a variety of chemical compounds to treat a disorder and/or disease. The chemical compound may include a pharmaceutical compound, such as an antirheumatic and/or antibiotic. In addition, the chemical compound may include compounds other than pharmaceutical compounds, such as antimicrobial polymers (e.g., functionalized polycarbonates). Multiple chemical compounds may be used in combination to achieve one or more synergistic effects that may enhance and/or facilitate one or more therapeutic treatments of the chemical compounds. Furthermore, the combination may comprise various types of chemical compounds. For example, one or more pharmaceutical compounds may be combined with one or more antimicrobial polymers in one or more combination therapies. In addition, treating the disease may include: inhibiting a disease, eradicating a disease, delaying a disease, palliating a disease, slowing the development of resistance to a treatment, combinations thereof, and/or the like. Moreover, a disease (e.g., infection) may be caused by one or more microorganisms (e.g., bacteria, such as gram-negative bacteria).
Unless otherwise indicated, materials used to facilitate the experiments, tables, graphs, figures, and/or the like described herein can be obtained from the following sources. The bacteria acinetobacter baumannii ("a. baumannii"), Enterobacter aerogenes ("e. aerogenes"), Escherichia coli ("e. coli"), pseudomonas aeruginosa ("p. aeruginosa") and/or klebsiella pneumoniae ("k. pneumoniae") are available from the american type culture collection ("ATCC"). Additionally, the antirheumatic auranofin is available from Sigma-Aldrich.
Fig. 1 is a diagram illustrating an exemplary non-limiting chemical formula 100 that may characterize one or more poly (guanidine carbonate) polymers that may be used in combination with one or more anti-rheumatic agents in one or more combination therapies against one or more bacteria (e.g., one or more antibiotic-resistant bacteria and/or gram-negative bacteria) according to one or more embodiments. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity.
The chemical structure 100 shown in fig. 1 can characterize one or more guanidinium-functionalized polycarbonate polymers that can be used in combination with one or more anti-rheumatic agents according to one or more embodiments described herein. As shown in fig. 1, chemical structure 100 may include one or more functional groups. For example, as shown in FIG. 1 as "R1"can represent a first functional group. The first functional group may include, for example, one or more of the following: biotin groups, glycosyl groups, alkyl groups and/or aryl groups. For example, one or more first functional groups (e.g., represented by "R")1"represents) may include, but is not limited to: carboxyl, carbonyl, ester, ether, ketone, amine, phosphine, urea, carbonate, alkenyl, hydroxyl, combinations thereof, and the like. In addition, "R" as shown in FIG. 12"may represent a second functional group. The second functional group may include, for example, one or more alkyl and/or aryl groups. For example, one or more second functional groups (e.g., represented by "R")2"represents) may include, but is not limited to: carboxyl, carbonyl, ester, ether, ketone, amine, phosphine, urea, carbonate, alkenyl, hydroxyl, combinations thereof, and the like. Also, "X" as shown in fig. 1 may represent one or more spacer structures. The one or more spacer structures may include, for example, one or more alkyl and/or aryl groups. For example, one or more spacer structures (e.g., represented by "X") can include, but are not limited to: carboxyl, carbonyl, ester, ether, ketone, amine, phosphine, urea, carbonate, alkenyl, hydroxyl, combinations thereof, and the like. Finally, "n" as shown in fig. 1 may represent a number greater than or equal to 1. For example, "n" may mean a range from, e.g., greater thanOr a number equal to 1 to less than or equal to 1000 (e.g., 20). As shown in fig. 1, the one or more polycarbonates characterized by chemical structure 100 can be functionalized with one or more guanidinium groups (e.g., bonded to the one or more polycarbonates via one or more spacer structures "X"). In one or more embodiments, the one or more guanidinium groups may be cationic (e.g., due to protonation of a primary amine of the guanidinium group).
Fig. 2 is a diagram illustrating exemplary non-limiting polymers that may be used in combination with one or more anti-rheumatic agents to facilitate one or more combination therapies according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity. For example, fig. 2 depicts a first exemplary polycarbonate 200 and/or a second exemplary polycarbonate 202. The first example polycarbonate 200 and/or the second example polycarbonate 202 may be characterized by a chemical structure 100. Also, as shown in fig. 2, "n" as shown may represent a number greater than or equal to 2 and less than or equal to 1000.
Fig. 3 is a diagram illustrating an exemplary non-limiting translocation mechanism 300 that may be implemented by one or more combination therapies that may employ one or more polymers characterized by chemical structure 100 in combination with one or more anti-rheumatic agents according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity. In one or more embodiments, translocation mechanism 300 can be directed to one or more bacteria. Exemplary bacteria may include gram negative bacteria and/or gram positive bacteria.
In one or more embodiments, one or more poly (guanidine carbonate) polymers (e.g., characterized by chemical structure 100) can undergo translocation mechanism 300 by one or more bacteria. In a first stage 302 of the translocation mechanism 300, one or more poly (guanidine carbonate) polymers (e.g., represented by circles and/or characterized by the chemical structure 100) may be attracted to a cell membrane 304 of a target microorganism (e.g., a bacterium). In one or more embodiments, the one or more poly (guanidine carbonate) polymers can be electrostatically attracted to the cell membrane 304. For example, one or more guanidinium groups of the poly (guanidine carbonate) polymer can be cationic and/or can be electrostatically attracted to one or more negative charges associated with cell membrane 304.
In the second stage 306, the one or more poly (guanidine carbonate) polymers may cross the cell membrane 304 of the target microorganism and enter the interior of the microorganism. For example, the cell membrane 304 (e.g., comprising a lipid bilayer) can separate the interior of the target microorganism from the environment surrounding the target microorganism. In various embodiments, the one or more guanidinium functional groups of the one or more poly (guanidinium carbonate) polymers may form one or more multidentate hydrogen bonds with one or more phosphate groups in the cell membrane 304. The one or more multidentate hydrogen bonds may neutralize the charge of the cell membrane 304 and thus may facilitate cell membrane 304 translocation. By entering the microorganism, the one or more poly (guanidine carbonate) polymers can associate with the inner leaflet of cell membrane 304 (e.g., as shown in fig. 3).
In the third stage 308, the one or more poly (guanidine carbonate) polymers can be released from the inner leaflet and dispersed within the cytoplasm of the microorganism. In the fourth stage 310, the one or more poly (guanidine carbonate) polymers may precipitate one or more proteins, enzymes, and/or genes (e.g., located in one or more DNA fragments 312 of the microorganism). For example, the one or more poly (guanidine carbonate) polymers can interact with one or more cytoplasmic proteins, enzymes, and/or genes of a microorganism and/or precipitate a cytoplasmic member.
In one or more embodiments, the one or more anti-rheumatic agents can treat rheumatoid arthritis by inhibiting thioredoxin reductase in the target cells. Thioredoxin reductase maintains intracellular levels of ROS. Thus, inhibition of thioredoxin reductase may result in increased ROS levels and apoptosis. For example, antirheumatic agents (2,3,4, 6-tetra-O-acetyl-1-thio-beta-D-glucopyranosyl-. kappa.S)1) (triethylphosphino) gold ("auranofin") can act by increasing ROS production in target cells. However, some microorganisms (e.g., gram-negative bacteria) may contain one or more agents that inhibit antirheumatic activityCytoplasmic members of agent function (e.g., thereby avoiding ROS production and enhancement of apoptosis).
In various embodiments, during translocation mechanism 300, one or more cytoplasmic members (e.g., proteins, enzymes, and/or genes) that can inhibit the function of one or more anti-rheumatic agents can be targeted for binding to and/or precipitation by one or more poly (guanidine carbonate) polymers. Thus, one or more poly (guanidine carbonate) polymers that can be characterized by chemical structure 100 can enhance the antimicrobial activity of one or more anti-rheumatic agents (e.g., auranofin) by binding and/or precipitating one or more cytoplasmic proteins, enzymes, and/or genes of a target microorganism. For example, the antibacterial activity of auranofin against gram-negative bacteria can be enhanced by a combination therapy comprising one or more poly (guanidine carbonate) polymers, which can be characterized by chemical structure 100, wherein cytoplasmic members that would otherwise inhibit auranofin function can be precipitated by the one or more poly (guanidine carbonate) polymers through translocation mechanism 300.
Fig. 4 is a graph illustrating an exemplary non-limiting histogram 400 that can illustrate the enhancement of auranofin antimicrobial activity resulting from a combination therapy comprising one or more poly (guanidine carbonate) polymers that can be characterized by chemical structure 100 according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity. Histogram 400 monitors ROS production in acinetobacter baumannii (a. baumann ni) cells treated with the lowest inhibitory concentration ("MIC") of auranofin, polymyxin e (colistin), first exemplary polycarbonate 200, and/or combinations thereof.
To generate histogram 400, 107A colony forming unit ("CFU")/mL (mL) of acinetobacter baumannii (a. baumann ni) was treated with auranofin, polymyxin e (colistin), first exemplary polycarbonate 200, and/or combinations thereof for 10 minutes. Cellular oxidative stress was measured using a CellRox green fluorescent probe. For example, a cell-permeable dye may exhibit fluorescence when oxidized by ROS. Thus, the greater the intracellular ROS production, the greater the fluorescence intensityLarge, the more apoptotic.
An "untreated" column may refer to ROS production in acinetobacter baumannii cells that have not been treated with auranofin, polymyxin E, the first exemplary polycarbonate 200, and/or combinations thereof. The "auranofin (MIC)" bar may represent ROS production in acinetobacter baumannii cells treated with 15.6 micrograms/mL (μ g/mL) MIC auranofin. A "auranofin" column may represent ROS production in Acinetobacter baumannii cells treated with half MIC of auranofin (e.g., 7.8 μ g/mL of auranofin). A "polymyxin E" column may represent ROS production in Acinetobacter baumannii cells treated with one-half MIC (1. mu.g/mL) of polymyxin E (e.g., 0.5. mu.g/mL of polymyxin E). The "pEt-20" column may represent ROS production in Acinetobacter baumannii cells treated with half the MIC (15.6. mu.g/mL) of the first exemplary polycarbonate 200 (e.g., 7.8. mu.g/mL of the first exemplary polycarbonate 200). The "first combination" column may represent ROS production in acinetobacter baumannii cells treated with a combination therapy comprising 7.8 μ g/mL auranofin and 7.8 μ g/mL first exemplary polycarbonate 200. The "second combination" column may represent ROS production in Acinetobacter baumannii cells treated with a combination therapy comprising 7.8 μ g/mL auranofin and 0.5 μ g/mL polymyxin E.
As shown in fig. 4, the antimicrobial activity of the antirheumatic agent auranofin can be greatly enhanced by combination therapy with one or more poly (guanidine carbonate) polymers characterized by chemical structure 100, such as the first exemplary polycarbonate 200. In addition, fig. 4 illustrates that combination therapies comprising auranofin and one or more poly (guanidine carbonate) polymers can have even greater antimicrobial effects than the use of poly (guanidine carbonate) polymers alone. Moreover, fig. 4 illustrates that combination therapies comprising auranofin and one or more poly (guanidine carbonate) polymers can have even greater antimicrobial effects than the use of the strong antimicrobial polymyxin E (e.g., alone or in combination therapy).
Fig. 5A-B and/or 6A-B are diagrams illustrating exemplary, non-limiting graphs that may further demonstrate the efficacy of combination therapies comprising one or more anti-rheumatic agents and a poly (guanidine carbonate) polymer in treating various bacterial infections, according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity.
Fig. 5A relates to treatment of acinetobacter baumannii with an exemplary combination therapy comprising auranofin and the first exemplary polycarbonate 200, wherein the MIC of the combination therapy is equal to 0.13 μ g/mL. Fig. 5B relates to treatment of enterobacter aerogenes with an exemplary combination therapy comprising auranofin and the first exemplary polycarbonate 200, wherein the MIC of the combination therapy is equal to 0.13 μ g/mL. FIG. 6A is directed to the treatment of Escherichia coli with an exemplary combination therapy comprising auranofin and a first exemplary polycarbonate 200, wherein the MIC of the combination therapy is equal to 3.90 μ g/mL. Fig. 6B relates to treatment of klebsiella pneumoniae with an exemplary combination therapy comprising auranofin and the first exemplary polycarbonate 200, wherein the MIC of the combination therapy is equal to 7.80 μ g/mL.
Figures 5A-B and/or 6A-B demonstrate that the antimicrobial activity against bacteria (e.g., gram negative bacteria) exhibited by the combination therapies described herein can be greater than the antimicrobial activity exhibited by antirheumatic agents (e.g., auranofin) or poly (guanidine carbonate) polymers alone. For example, auranofin typically exhibits no or little antimicrobial activity against gram-negative bacteria; however, one or more of the combination therapies described herein can enhance the antimicrobial activity of auranofin such that the antimicrobial function (e.g., increased ROS production within the target cell) of auranofin can effectively treat (e.g., inhibit) gram-negative bacteria. For example, the translocation mechanism 300 exhibited by one or more of the poly (guanidine carbonate) polymers described herein may have a synergistic effect with the thioredoxin reductase inhibition exhibited by auranofin; thus, the antimicrobial activity of auranofin is enhanced by combination therapy with one or more of the various poly (guanidine carbonate) polymers described herein.
Fig. 7 is a flow chart illustrating an exemplary, non-limiting method 700 for one or more combination therapies comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity.
At 702, the method 700 can include enhancing antimicrobial activity of one or more anti-rheumatic agents by a combination therapy, wherein the combination therapy can include one or more anti-rheumatic agents and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups. For example, the one or more anti-rheumatic agents may be auranofin and/or the one or more polycarbonate polymers may be characterized by chemical structure 100 (e.g., first exemplary polycarbonate 200 and/or second exemplary polycarbonate 202). In various embodiments, the antimicrobial activity can be an antimicrobial activity effective to treat one or more bacterial infections, such as a gram-negative bacterial infection.
In 704, the method 700 can include interacting the one or more polycarbonate polymers with one or more cytoplasmic members of a microorganism targeted for antimicrobial activity. For example, the one or more polycarbonate polymers can implement a translocation mechanism (e.g., translocation mechanism 300) to bind and/or precipitate one or more cytoplasmic members. Exemplary cytoplasmic members may include, but are not limited to: proteins, enzymes and/or genes. In various embodiments, the interaction with the one or more polycarbonate polymers at 704 may have a synergistic effect with the antimicrobial activity of the one or more anti-rheumatic agents. For example, the one or more cytoplasmic members targeted by the interaction at 704 can be cytoplasmic members that would otherwise inhibit one or more antimicrobial functions of one or more anti-rheumatic agents; thereby facilitating an enhancement of antimicrobial activity at 702. In one or more embodiments, the one or more anti-rheumatic agents may be auranofin, and the combination therapy may cause auranofin to exhibit antimicrobial activity against gram-negative bacteria.
Fig. 8 is a flow chart illustrating an exemplary, non-limiting method 800 for one or more combination therapies comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity.
In 802, method 800 can comprise enhancing antimicrobial activity of one or more anti-rheumatic agents by a combination therapy, wherein the combination therapy can comprise the one or more anti-rheumatic agents and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups. For example, the one or more anti-rheumatic agents may be auranofin and/or the one or more polycarbonate polymers may be characterized by chemical structure 100 (e.g., first exemplary polycarbonate 200 and/or second exemplary polycarbonate 202). In various embodiments, the antimicrobial activity can be an antimicrobial activity effective to treat one or more bacterial infections, such as a gram-negative bacterial infection.
In 804, the method 800 may include translocating one or more polycarbonate polymers across the cell membrane 304. For example, the shifting at 804 may be performed in accordance with the shifting mechanism 300 described herein. For example, cell membrane 304 may be a membrane of a microorganism targeted by the antimicrobial activity of the one or more anti-rheumatic agents.
At 806, method 800 can include interacting the one or more polycarbonate polymers with one or more cytoplasmic members of a microorganism targeted for antimicrobial activity. For example, after the translocation at 804, the one or more polycarbonate polymers can bind and/or precipitate one or more cytoplasmic members. Exemplary cytoplasmic members may include, but are not limited to: proteins, enzymes and/or genes. In various embodiments, the one or more cytoplasmic members targeted by the interaction at 806 can be cytoplasmic members that would otherwise inhibit one or more antimicrobial functions of the one or more anti-rheumatic agents.
At 808, method 800 can include increasing ROS production in the microorganism of one or more anti-rheumatic agents. For example, one or more anti-rheumatic agents may inhibit thioredoxin reductase in microorganisms. In various embodiments, the increased ROS production at 808 may be produced, at least in part, by a shift at 804 and/or an interaction at 806 of one or more polycarbonate polymers. Thus, the activity of one or more polycarbonate polymers may have a synergistic effect with the activity of one or more anti-rheumatic agents, thereby facilitating the enhancement of antimicrobial activity.
Fig. 9 is a flow chart illustrating an exemplary, non-limiting method 900 for one or more combination therapies comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity.
At 902, method 900 can comprise treating a bacterial infection by a combination therapy comprising one or more antirheumatic agents and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups, wherein the one or more polycarbonate polymers can enhance the antibacterial activity of the one or more antirheumatic agents. For example, the one or more anti-rheumatic agents may be auranofin and/or the one or more polycarbonate polymers may be characterized by chemical structure 100 (e.g., first exemplary polycarbonate 200 and/or second exemplary polycarbonate 202). Also, exemplary bacterial infections may include, but are not limited to, infections of acinetobacter baumannii (a. baumannii), enterobacter aerogenes (e.coli), escherichia coli (e.coli), klebsiella pneumoniae (k. pneumoniae), and/or combinations thereof.
At 904, method 900 can increase ROS production within one or more bacteria of a bacterial infection via one or more antirheumatic agents. For example, one or more polycarbonate polymers of the combination therapy may contribute to and/or promote the inhibitory activity of one or more anti-rheumatic agents against thioredoxin reductase. Thus, the one or more anti-rheumatic agents may exhibit enhanced antibacterial activity. For example, auranofin can exhibit antibacterial activity against gram-negative bacteria.
Fig. 10 is a flow chart illustrating an exemplary, non-limiting method 1000 for one or more combination therapies comprising one or more poly (guanidine carbonate) polymers and an anti-rheumatic agent according to one or more embodiments described herein. Repeated descriptions of like elements employed in other embodiments described herein are omitted for the sake of brevity.
In 1002, method 1000 can include treating a bacterial infection by a combination therapy comprising one or more antirheumatic agents and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups, wherein the one or more polycarbonate polymers can enhance the antibacterial activity of the one or more antirheumatic agents. For example, the one or more anti-rheumatic agents may be auranofin and/or the one or more polycarbonate polymers may be characterized by chemical structure 100 (e.g., first exemplary polycarbonate 200 and/or second exemplary polycarbonate 202). In addition, exemplary bacterial infections can include, but are not limited to, infections of acinetobacter baumannii, enterobacter aerogenes, escherichia coli, klebsiella pneumoniae, and/or combinations thereof, and the like.
At 1004, the method 1000 may include translocating the one or more polycarbonate polymers across a cell membrane 304 of the one or more bacteria of the bacterial infection. For example, the shifting at 1004 may be performed in accordance with shifting mechanism 300 described herein. For example, the cell membrane 304 may be a membrane of a bacterium targeted by the antibacterial activity of the one or more antirheumatic agents.
At 1006, method 800 can include precipitating one or more cytoplasmic members of the one or more bacteria via interaction between the one or more cytoplasmic members and the one or more polycarbonate polymers. For example, after the displacement at 1004, one or more polycarbonate polymers can bind to and/or precipitate one or more cytoplasmic members. Exemplary cytoplasmic members may include, but are not limited to: proteins, enzymes and/or genes. In various embodiments, the one or more cytoplasmic members targeted by the interaction at 1006 may be cytoplasmic members that would otherwise inhibit one or more antimicrobial functions of the one or more anti-rheumatic agents.
At 1008, method 1000 may include increasing ROS production within one or more bacteria of one or more anti-rheumatic agents. For example, the one or more anti-rheumatic agents may inhibit thioredoxin reductase in the microorganism. In various embodiments, the increased ROS production at 1008 can be, at least in part, produced by a shift at 1004 and/or an interaction at 1006 of one or more polycarbonate polymers. Thus, the activity of one or more polycarbonate polymers may have a synergistic effect with the activity of one or more anti-rheumatic agents, thereby facilitating the enhancement of antimicrobial activity.
Throughout this disclosure, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or. In other words, "X employs a or B" is intended to mean any of the natural inclusive permutations, unless specified otherwise or clear from the context. In other words, if X employs A; x is B; or X employs both A and B, then "X employs A or B" is satisfied under any of the foregoing instances. Furthermore, the terms themselves, as used in this specification and the drawings, should generally be construed to mean "one or more" and "one or more" unless specified otherwise or clear from context to be directed to a singular form. The terms "example" and/or "exemplary" as used herein are used to mean serving as an example, instance, or illustration. For the avoidance of doubt, the subject matter disclosed herein is not limited by these examples. Moreover, any aspect or design described herein as "exemplary" and/or "exemplary" is not necessarily to be construed as preferred or advantageous over other aspects or designs, nor is it meant to preclude equivalent exemplary structures and techniques known to those of ordinary skill in the art.
It is, of course, not possible to describe every conceivable combination of components, products, and/or methods for purposes of describing the present disclosure, but one of ordinary skill in the art may recognize that many further combinations and permutations of the present disclosure are possible. Furthermore, to the extent that the terms "includes," "has," and the like are used in the detailed description, the claims, the appendices, and the accompanying drawings, these terms are intended to be inclusive in a manner similar to the term "comprising" as "comprising" is interpreted when employed as a transitional word in a claim. The description of the various embodiments has been presented for purposes of illustration but is not intended to be exhaustive or limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope of the described embodiments. The terminology used herein was chosen to best explain the principles of the embodiments, the practical application, or technical improvements over the prior art on the market, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Claims (20)
1. A chemical composition comprising:
a polycarbonate polymer functionalized with a guanidinium functionality; and
an anti-rheumatic agent, wherein said polycarbonate polymer enhances the antimicrobial activity of said anti-rheumatic agent.
2. The chemical composition of claim 1 wherein the anti-rheumatic agent is (2,3,4, 6-tetra-O-acetyl-1-thio- β -D-glucopyranosyl- κ S1) (triethylphosphino) gold.
3. The chemical composition of claim 2 wherein the antimicrobial activity inhibits gram negative bacteria.
4. The chemical composition of claim 2, wherein the polycarbonate polymer enhances antimicrobial activity by translocating across cell membranes and interacting with cytoplasmic members of a target microorganism.
5. The chemical composition of claim 4, wherein the cytoplasmic member is selected from the group consisting of a protein, an enzyme, and a gene.
6. The chemical composition of claim 4, wherein the antimicrobial activity comprises increasing reactive oxygen species production within a target microorganism of the anti-rheumatic agent.
7. The chemical composition of claim 2, wherein the polycarbonate polymer has a structure characterized by the formula:
wherein "R1"corresponds to a compound selected from the group consisting ofThe first functional group of (a): a biotin group, a glycosyl group, a first alkyl group, and a first aryl group;
wherein "R2"corresponds to a second functional group selected from a second group consisting of hydrogen, a second alkyl group, and a second aryl group;
wherein "X" corresponds to a spacer structure selected from a third group consisting of a third alkyl group and a third aryl group; and
wherein "n" corresponds to an integer greater than or equal to 1 and less than or equal to 1000.
8. A method, comprising:
enhancing the antimicrobial activity of an anti-rheumatic agent by a combination therapy, wherein the combination therapy comprises an anti-rheumatic agent and a polycarbonate polymer functionalized with a guanidinium functionality.
9. The method of claim 8, wherein the anti-rheumatic agent is (2,3,4, 6-tetra-O-acetyl-1-thio- β -D-glucopyranosyl- κ S1) (triethylphosphino) gold.
10. The method of claim 9, wherein enhancing the antimicrobial activity of the anti-rheumatic agent comprises translocation of the polycarbonate polymer across a cell membrane and interaction of the polycarbonate polymer with a cytoplasmic member of the microorganism targeted by the antimicrobial activity, wherein the cytoplasmic member is selected from the group consisting of a protein, an enzyme, and a gene.
11. The method of claim 10, wherein the antimicrobial activity comprises increasing reactive oxygen species production within microorganisms of the antirheumatic agent.
12. The method of claim 9, wherein the antimicrobial activity inhibits gram negative bacteria.
13. The method of claim 8, wherein the combination therapy reduces the occurrence of resistance to the antimicrobial activity by a microorganism targeted by the anti-rheumatic agent.
14. The method of claim 9, wherein the polycarbonate polymer has a structure characterized by the formula:
wherein "R1"corresponds to a first functional group selected from the first group consisting of: a biotin group, a glycosyl group, a first alkyl group, and a first aryl group;
wherein "R2"corresponds to a second functional group selected from a second group consisting of hydrogen, a second alkyl group, and a second aryl group;
wherein "X" corresponds to a spacer structure selected from a third group consisting of a third alkyl group and a third aryl group; and
wherein "n" corresponds to an integer greater than or equal to 1 and less than or equal to 1000.
15. A method, comprising:
treating a bacterial infection by a combination therapy comprising an antirheumatic agent and a polycarbonate polymer functionalized with guanidinium functional groups, wherein the polycarbonate polymer enhances the antibacterial activity of the antirheumatic agent.
16. The method of claim 15, wherein the anti-rheumatic agent is (2,3,4, 6-tetra-O-acetyl-1-thio- β -D-glucopyranosyl- κ S1) (triethylphosphino) gold.
17. The method of claim 16, further comprising:
the polycarbonate polymer translocates across the cell membrane of the bacterially infected bacteria; and
precipitating a cytoplasmic member of the bacterium by interaction between the cytoplasmic member and the polycarbonate polymer, wherein the cytoplasmic member is selected from the group consisting of a protein, an enzyme, and a gene.
18. The method of claim 17, further comprising:
increasing reactive oxygen species production in bacteria via the antirheumatic agent.
19. The method of claim 18, wherein the bacterium is a gram-negative bacterium.
20. The method of claim 19, wherein the polycarbonate polymer has a structure characterized by the formula:
wherein "R1"corresponds to a first functional group selected from the first group consisting of: a biotin group, a glycosyl group, a first alkyl group, and a first aryl group;
wherein "R2"corresponds to a second functional group selected from a second group consisting of hydrogen, a second alkyl group, and a second aryl group;
wherein "X" corresponds to a spacer structure selected from a third group consisting of a third alkyl group and a third aryl group; and
wherein "n" corresponds to an integer greater than or equal to 1 and less than or equal to 1000.
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| CN1694894A (en) * | 2001-11-14 | 2005-11-09 | 森托科尔公司 | Anti-IL-6 antibodies, compositions, methods and uses |
| US20080312172A1 (en) * | 2001-11-14 | 2008-12-18 | Jill Giles-Komar | Anti-IL-6 Antibodies, Compositions, Methods and Uses |
| CN103998035A (en) * | 2011-12-19 | 2014-08-20 | 阿雷斯贸易股份有限公司 | Pharmaceutical compositions comprising glitazones and NRF2 activators |
| CN108430482A (en) * | 2015-11-10 | 2018-08-21 | 伊丽莎白·麦克纳 | The control of cell Redox level |
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| JP2022543409A (en) | 2022-10-12 |
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| JP2022543408A (en) | 2022-10-12 |
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| GB2601667A (en) | 2022-06-08 |
| WO2021024057A1 (en) | 2021-02-11 |
| WO2021024054A1 (en) | 2021-02-11 |
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