JP7481077B2 - Combination Therapy to Achieve Improved Antibacterial Activity - Google Patents

Description

The subject disclosure relates to the use of combination therapies to enhance the antimicrobial activity of therapeutic compounds, and more specifically, to combination therapies that include one or more poly(guanidinium carbonate) polymers and an antirheumatic drug (e.g., auranofin).

The following presents a summary to provide a basic understanding of one or more of the present inventions. This summary is not intended to define key or critical elements or to delimit any scope of particular embodiments or any scope of the claims. Its sole purpose is to present the concepts in a simplified form as a prelude to the more detailed description presented later. In one or more embodiments described herein, chemical compositions or methods or both are described for one or more combination therapies comprising one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin).

According to an embodiment, a chemical composition is provided. The chemical composition can include a polycarbonate polymer functionalized with guanidinium functional groups. The chemical composition can also include an antirheumatic drug, and the polycarbonate polymer can enhance the antimicrobial activity of the antirheumatic drug.

According to the present embodiment, a method is provided. The method includes enhancing the antibacterial activity of an antirheumatic drug by a combination therapy. The combination therapy can include an antirheumatic drug and a polycarbonate polymer functionalized with guanidinium functional groups.

According to an embodiment, a method is provided. The method can include treating a bacterial infection via a combination therapy that includes an antirheumatic drug and a polycarbonate polymer functionalized with guanidinium functional groups. Further, the polycarbonate polymer can enhance the antibacterial activity of the antirheumatic drug.

The invention will now be described, by way of example only, with reference to a preferred embodiment as illustrated in the following drawings:

FIG. 1 illustrates non-limiting example chemical formulas characterizing poly(guanidinium carbonate) that may be included in combination therapy with one or more anti-rheumatic drugs (e.g., auranofin) according to one or more embodiments described herein. FIG. 2 illustrates example, non-limiting poly(guanidinium carbonate) structures that may be included in combination therapy with one or more anti-rheumatic drugs (e.g., auranofin) according to one or more embodiments described herein. FIG. 3 illustrates an example, non-limiting translocation mechanism that can be implemented by one or more poly(guanidinium carbonate) polymers included in a combination therapy with one or more anti-rheumatic drugs (e.g., auranofin) according to one or more embodiments described herein. FIG. 4 shows a non-limiting example bar graph that may illustrate the effect of a combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin) according to one or more embodiments described herein. FIG. 5A shows a non-limiting example bar graph that can illustrate the effect of a combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin) according to one or more embodiments described herein. FIG. 5B shows a non-limiting example bar graph that can illustrate the effect of a combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin) according to one or more embodiments described herein. FIG. 6A shows a non-limiting example bar graph that can illustrate the effect of a combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin) according to one or more embodiments described herein. FIG. 6B shows a non-limiting example bar graph that can show the effect of a combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin) according to one or more embodiments described herein. FIG. 7 shows a non-limiting flow diagram of an example for enhancing the antibacterial activity of one or more anti-rheumatic drugs (eg, auranofin) according to one or more embodiments. FIG. 8 shows a non-limiting flow diagram of an example for enhancing the antibacterial activity of one or more anti-rheumatic drugs (eg, auranofin) according to one or more embodiments. FIG. 9 shows a non-limiting flow diagram of an example for enhancing the antibacterial activity of one or more anti-rheumatic drugs (eg, auranofin) according to one or more embodiments. FIG. 10 shows a non-limiting flow diagram of an example method for treating bacterial infections with a combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug (e.g., auranofin) according to one or more embodiments described herein.

The following detailed description is merely illustrative and is not intended to limit the embodiments or applications or both or the uses of the embodiments. Furthermore, there is no intention to be limiting of any express or implied statements made in the Background or Summary section above or in the 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 will be apparent, however, that in various instances one or more embodiments may be practiced without these specific details.

There are many challenges associated with commercializing a new therapeutic chemical composition. For example, commercializing a new chemical composition can cost an average of $1.52 billion, take an average of 7 to 15 years, or have a 90% failure rate, or a combination thereof. In addition, regulatory restrictions may be imposed on a newly introduced therapeutic chemical composition. For example, a newly introduced antibiotic may have regulatory restrictions in view of its availability as a prescription drug or for agricultural use, or both, to minimize the development of antibiotic resistance among bacteria.

Various embodiments described herein may relate to repositioning one or more anti-rheumatic drugs as antimicrobial agents (e.g., having antibacterial activity) using combination therapy using one or more poly(guanidinium carbonate) polymers according to one or more embodiments described herein. One or more embodiments may be considered a chemical composition including one or more polycarbonate polymers functionalized with guanidinium functional groups and one or more anti-rheumatic drugs (e.g., auranofin). The one or more polycarbonate polymers may enhance the antibacterial activity of the one or more anti-rheumatic drugs. For example, the one or more polycarbonate polymers may interact with a microorganism of interest by a translocation mechanism and precipitation of cytosolic members. Precipitation of one or more cytosolic members allows for antibacterial activity by one or more anti-rheumatic drugs that would otherwise be inhibited. For example, the one or more polycarbonate polymers may enable the one or more anti-rheumatic drugs to increase the production of reactive oxygen species ("ROS") in a microorganism. The one or more polycarbonate polymers may thereby enhance the antimicrobial activity of the one or more anti-rheumatic drugs, or enable the repositioning of the one or more anti-rheumatic drugs as broad spectrum antimicrobial agents for treating bacterial infections, or both.

As used herein, the term "combination therapy" can refer to the use of multiple chemical compositions to treat a disease or illness or both. The chemical compositions can include pharmaceutical compositions, such as antirheumatic drugs or antibiotics, or both. Additionally, the chemical compositions can include compositions other than pharmaceutical compositions, such as antimicrobial polymers (e.g., functionalized polycarbonates). Multiple chemical compositions can be used in combination to achieve one or more synergistic effects that enable, facilitate, or both the therapeutic treatment of one or more of the chemical compositions. In addition, the combination can include various types of chemical compositions. For example, in one or more combination therapies, one or more pharmaceutical compositions can be combined with one or more antimicrobial polymers. Additionally, treating a disease can include inhibiting a disease, eradicating a disease, delaying a disease, ameliorating a disease, reducing the development of resistance to treatment by a disease, and the like, or combinations thereof. Additionally, a disease (e.g., an infection) can be caused by one or more microorganisms (e.g., bacteria, such as gram-negative bacteria).

Unless otherwise stated, materials used to facilitate the experiments, tables, charts, figures, and the like, or combinations thereof, described herein may be obtained from the following sources: the bacteria Acinetobacter baumannii ("A. baumannni"), Enterobacter aerogenes ("E. aerogenes"), Escherichia coli ("E. coli"), Pseudomonas aeruginosa ("P. aeruginosa"), or Klebsiella pneumoniae ("K. pneumoniae") may be obtained from the American Type Culture Collection ("ATCC"); and the anti-rheumatic drug auranofin may be obtained from Sigma-Aldrich.

1 shows an example, non-limiting chemical structure 100 for characterizing one or more poly(guanidinium carbonate) polymers that can be used in combination with one or more antirheumatic drugs in one or more combination therapies directed against one or more bacteria (e.g., one or more antibiotic-resistant bacteria or gram-negative bacteria or both) according to one or more embodiments. Repetition of similar elements used in other embodiments described herein is 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 drugs according to one or more embodiments described herein. As shown in FIG. 1, the chemical structure 100 can include one or more functional groups. For example, "R ¹ " in FIG. 1 can represent a first functional group. The first functional group can include, for example, one or more of: a biotin group, a sugar group, an alkyl group, or an aryl group, or a combination thereof. For example, the one or more first functional groups (e.g., represented by "R ¹ ") can include, but are not limited to, a carboxyl group, a carbonyl group, an ester group, an ether group, a ketone group, an amine group, a phosphine group, a uric acid group, a carbonate group, an alkenyl group, a hydroxyl group, or a combination thereof, etc. Additionally, "R ² " shown in FIG. 1 can represent a second functional group. The second functional group can include, for example, one or more alkyl groups or aryl groups, or both. For example, the one or more second functional groups (e.g., represented by "R ² ") can include, but are not limited to, a carboxyl group, a carbonyl group, an ester group, an ether group, a ketone group, an amine group, a phosphine group, a urea group, a carbonate group, an alkenyl group, a hydroxyl group, and the like, or a combination thereof. Furthermore, "X" in FIG. 1 can represent one or more spacer structures. The one or more spacer structures can include, for example, one or more alkyl or aryl groups, or both. For example, the one or more spacer structures (e.g., represented by "X") can include, but are not limited to, a carboxyl group, a carbonyl group, an ester group, an ether group, a ketone group, an amine group, a phosphine group, a urea group, a carbonate group, an alkenyl group, a hydroxyl group, and the like, or a combination thereof. Finally, "n" in FIG. 1 can represent a number equal to or greater than 1. For example, "n" can represent a number ranging from, for example, 1 to 1000 (e.g., 20). 1, one or more polycarbonates characterized by chemical structure 100 can be functionalized with one or more guanidinium groups thereon (e.g., one or more polycarbonates linked via one or more spacer structures "X"). In one or more embodiments, one or more of the guanidinium groups can be cationic (e.g., by protonation of the primary amine of the guanidinium group).

Figure 2 shows a diagram of a non-limiting example of a compound that may be used in combination with one or more anti-rheumatic drugs to facilitate one or more combination therapies in one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the sake of brevity. For example, Figure 2 shows a first example carbonate 200 or a second example polycarbonate 202, or both. The first example polycarbonate 200 or the second example polycarbonate 202, or both, may be characterized by a chemical structure 100. Also, as shown in Figure 2, the "n" shown represents a number that is 2 or more and 1000 or less.

Figure 3 shows a diagram of a non-limiting example translocation mechanism 300 that can be implemented with one or more combination therapies, where one or more polymers characterized by chemical structure 100 can be used in combination with one or more anti-rheumatic drugs according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the sake of brevity. In one or more embodiments, the translocation mechanism 300 can be directed to one or more bacteria. Exemplary bacteria can include gram-negative or gram-positive bacteria or both.

In one or more embodiments, one or more poly(guanidinium carbonate) polymers (e.g., characterized by chemical structure 100) can perform a translocation mechanism 300 with one or more bacteria. In a first stage 302 of the translocation mechanism 300, one or more poly(guanidinium carbonate) polymers (e.g., represented by a circle or chemical structure 100, or both) can attach to a cell membrane 304 of a target microorganism (e.g., bacteria). In one or more embodiments, one or more poly(guanidinium carbonate) polymers can electrostatically attach to the cell membrane 304. For example, one or more guanidinium groups of the poly(guanidinium carbonate) polymers can be cationic or electrostatically attracted to one or more negative charges associated with the cell membrane 304, or both.

In a second stage 306, the one or more poly(guanidinium carbonate) polymers can penetrate the cell membrane of the target microorganism and enter the interior of the bacterium. Illustratively, a cell membrane 304 (e.g., a lipid bilayer) can separate the interior of the target microorganism from the environment surrounding the target microorganism. In various embodiments, one or more guanidinium functional groups of the one or more poly(guanidinium carbonate) polymers can 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 can neutralize the charge of the cell membrane 304, thus inducing translocation of the cell membrane 304. Upon entering the microorganism, the one or more poly(guanidinium carbonate) polymers attach to the inner leaflet of the cell membrane 304 (e.g., as shown in FIG. 3).

In a third stage 308, one or more poly(guanidinium carbonate) polymers are released from the inner leaflet dispersed within the cytoplasm of the microorganism. In stage 310, the one or more poly(guanidinium carbonate) polymers can precipitate one or more proteins, enzymes, or genes (e.g., disposed within one or more DNA segments 312 of the microorganism), or a combination thereof. Illustratively, the one or more poly(guanidinium carbonate) polymers can interact with one or more cytosolic proteins, enzymes, genes, or a combination thereof of the microorganism, or can precipitate cytosolic members, or a combination thereof.

In one or more embodiments, the one or more anti-rheumatic drugs can treat rheumatoid arthritis by inhibiting thioredoxin reductase in target cells. Thioredoxin reductase can maintain intracellular levels of ROS. Thus, inhibition of thioredoxin reductase can result in high levels of ROS and cellular apoptosis. An exemplary anti-rheumatic drug, (2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranosato- ^κS1 )(triethylphosphoranylidene)gold ("auranofin"), functions by increasing ROS production in target cells. However, some microorganisms (e.g., gram-negative bacteria) may contain one or more cytosolic members that can inhibit the function of antirheumatic drugs (e.g., thereby avoiding increased ROS production and cell apoptosis).

In various embodiments, one or more cytosolic members (e.g., proteins, enzymes, or genes, or combinations thereof) capable of inhibiting the function of one or more antirheumatic drugs can be targeted for binding or deposition, or both, by one or more poly(guanidinium carbonate) polymers during the translocation mechanism 300. Thus, one or more poly(guanidinium carbonate) polymers characterized by chemical structure 100 can enhance the antibacterial activity of one or more antirheumatic drugs (e.g., auranofin) by binding to or depositing one or more cytosolic proteins, enzymes, or genes, or combinations thereof, of the target microorganism. For example, the antibacterial activity of auranofin against gram-negative bacteria can be enhanced by a combination therapy that includes one or more poly(guanidinium carbonate) polymers characterized by chemical structure 100, where cytosolic members that would otherwise inhibit the function of auranofin can be precipitated by one or more poly(guanidinium carbonate) polymers through a translocation mechanism 300.

4 shows a diagram of a non-limiting example bar graph 400 that can illustrate the improved antibacterial activity of auranofin resulting from combination therapy using one or more poly(guanidinium carbonate) polymers according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the sake of brevity. The bar graph 400 measures ROS generated in A. baumannii cells treated with auranofin, colistin, minimum inhibitory concentration ("MIC") of the first example polycarbonate 200, or a combination thereof.

To obtain bar graph 400, ¹⁰⁷ colony forming units ("CFU") per milliliter (mL) of A. baumannii were treated with auranofin, colistin, polycarbonate 200 of the first example, or a combination thereof. The CellRox Green fluorescent probe was used to measure cellular oxidative stress. For example, the cell permeable dye can generate fluorescence upon oxidation by ROS. Thus, a higher amount of ROS generation in cells indicates stronger fluorescence intensity and higher cell apoptosis.

The "Untreated" bar can represent ROS generation in A. baumannii cells that are not treated with auranofin, colistin, polycarbonate 200 of the first example, or a combination thereof. The "Auranofin (MIC)" bar can represent ROS generation in A. baumannii cells that are treated with 15.6 micrograms per milliliter (μg/mL) of auranofin. The "Auranofin" bar can represent ROS generation in A. baumannii cells that are treated with half the MIC of auranofin (e.g., auranofin, 7.8 μg/mL). The "Colistin" bar can represent ROS generation in A. baumannii cells that are treated with half the MIC of colistin (e.g., colistin, 0.5 μg/mL). The "pEt_20" bar can represent ROS generation in A. baumannii cells treated with half the MIC of polycarbonate 200 of the first example (e.g., polycarbonate 200 of the first example, 15.6 μg/mL). The "first combination" bar can represent ROS generation in A. baumannii cells treated with 7.8 μg/mL auranofin and 7.8 μg/mL polycarbonate 200 of the first example. The "second combination" bar can represent ROS generation in A. baumannii cells treated with 7.8 μg/mL auranofin and 0.5 μg/mL colistin.

As shown in FIG. 4, the antibacterial activity of the antirheumatic drug, auranofin, can be significantly improved through combination therapy using one or more poly(guanidinium carbonate) polymers characterized by chemical structure 100 (e.g., first example polycarbonate 200). In addition, FIG. 4 shows that combination therapy including auranofin and one or more poly(guanidinium carbonate) polymers can have even higher antibacterial activity than the use of poly(guanidinium carbonate) polymers alone. Furthermore, FIG. 4 shows that combination therapy including auranofin and one or more poly(guanidinium carbonate) polymers has even higher antibacterial activity than the use of colistin, a potent antibacterial agent (e.g., alone or in both combination therapies).

5A-B or 6A-B or both show non-limiting example graphical illustrations that may further illustrate the efficacy of combination therapies including one or more anti-rheumatic drugs and poly(guanidinium carbonate) polymers in treating various bacterial infections according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the sake of brevity.

5A relates to the treatment of A. baunanni using an exemplary combination therapy comprising auranofin and the first example polycarbonate 200, where the MIC of the combination therapy is equal to 0.13 μg/mL. FIG. 5B relates to the treatment of E. aerogenes using an exemplary combination therapy comprising auranofin and the first example polycarbonate 200, where the MIC of the combination therapy is equal to 0.13 μg/mL. FIG. 6A relates to the treatment of E. coli using an exemplary combination therapy comprising auranofin and the first example polycarbonate 200, where the MIC of the combination therapy is equal to 3.90 μg/mL. FIG. 6B relates to the treatment of K. japonica using an exemplary combination therapy comprising auranofin and the first example polycarbonate 200. pneumoniae, and the MIC of the combination therapy is equal to 7.80 μg/mL.

5A-B or 6A-B, or both, show that the combination therapies described herein can exhibit greater antibacterial activity against bacteria (e.g., gram-negative bacteria) than would otherwise be exhibited by an antirheumatic drug (e.g., auranofin) or a poly(guanidinium carbonate) polymer alone. For example, auranofin typically exhibits little or no antibacterial activity against gram-negative bacteria, but one or more combination therapies described herein can enhance the antibacterial activity of auranofin, making the antibacterial function of auranofin (e.g., increasing ROS production in target cells) effective in treating (e.g., inhibiting) gram-negative bacteria. For example, the translocation mechanism 300 exhibited by one or more poly(guanidinium carbonate) polymers described herein may have a synergistic effect with the thioredoxin reductase inhibition exhibited by auranofin, thereby enhancing the antimicrobial activity of auranofin via combination therapy using one or more of the various poly(guanidinium carbonate) polymers described herein.

Figure 7 shows a flow diagram of a non-explanatory example method 700 of one or more combination therapies including one or more poly(guanidinium carbonate) polymers and an antirheumatic drug, according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the purposes of brevity.

At 702, the method 700 includes enhancing the antibacterial activity of one or more antirheumatic drugs by a combination therapy, where the combination therapy includes one or more antirheumatic drugs and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups. For example, the one or more antibacterial agents can be auranofin, or the one or more polycarbonate polymers can be characterized by chemical structure 100 (e.g., polycarbonate 200 of the first example or polycarbonate 202 of the second example or both), or both. In various embodiments, the antibacterial activity is antibacterial activity effective in treating one or more bacterial infections, such as gram-negative bacteria.

At 704, the method 700 can include interacting one or more polycarbonate polymers with one or more cytosolic 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 to or precipitate one or more cytosolic members, or both. Example cytosolic members can include, but are not limited to, proteins, enzymes, or genes, or combinations thereof. In various embodiments, the interaction at 704 by the one or more polycarbonate polymers can have a synergistic effect with the antimicrobial activity of one or more antirheumatic drugs. For example, the one or more cytosolic members targeted by the interaction at 704 can be cytosolic members that would otherwise inhibit one or more antimicrobial functions of the one or more antirheumatic drugs, thereby facilitating enhanced antimicrobial activity at 702. In one or more embodiments, the one or more antirheumatic drugs is auranofin, and the combination therapy can enable auranofin to exhibit antibacterial activity against gram-negative bacteria.

Figure 8 shows a flow diagram of a non-limiting example method 800 of one or more combination therapies including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the purposes of brevity.

At 802, the method 800 can include enhancing the antibacterial activity of one or more antirheumatic drugs by a combination therapy, where the combination therapy can include one or more antirheumatic drugs and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups. For example, the one or more antirheumatic drugs can be auranofin, or the one or more polycarbonate polymers can be characterized by chemical structure 100 (e.g., polycarbonate 200 of the first example or polycarbonate 202 of the second example, or both), or both. In various embodiments, the antibacterial activity is antibacterial activity effective in treating one or more bacterial infections, such as gram-negative bacteria.

The method 800 includes, at 804, translocating one or more polycarbonate polymers through a cell membrane 304. For example, the translocation at 804 can be accomplished according to the translocation mechanism 300 described herein. By way of example, the cell membrane 304 can be a cell membrane of a microorganism targeted for the antimicrobial activity of one or more antirheumatic drugs.

The method 800 includes, at 806, interacting one or more polycarbonate polymers with one or more cytosolic members of a targeted microorganism with antimicrobial activity. For example, following translocation 804, the one or more polycarbonate polymers bind or precipitate or both the one or more cytosolic members. Exemplary cytosolic members may include, but are not limited to, proteins, enzymes, or genes, or combinations thereof. In various embodiments, the one or more cytosolic members targeted by the interaction at 806 may be cytosolic members that would otherwise inhibit one or more antimicrobial functions of one or more antirheumatic drugs.

At step 808, the method 800 can increase ROS production in the microorganism with one or more anti-rheumatic drugs. For example, the one or more anti-rheumatic drugs can inhibit thioredoxin reductase in the microorganism. In various embodiments, increasing ROS production at 808 can be enabled, at least in part, by translocation at 804 or interaction at 806, or both, effected by the one or more polycarbonate polymers. Thus, the activity of the one or more polycarbonate polymers can have a synergistic effect with the activity of the one or more anti-rheumatic drugs, thereby facilitating improved antimicrobial activity.

Figure 9 is a flow diagram illustrating a non-limiting example method 900 for combination therapy including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the purposes of brevity.

The method 900 can include, at 902, treating a bacterial infection via a combination therapy including one or more anti-rheumatic drugs and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups, where the one or more polycarbonate polymers can enhance the anti-bacterial activity of the one or more anti-rheumatic drugs. For example, the one or more anti-bacterial drugs can be auranofin, or the one or more polycarbonate polymers can be characterized by chemical structure 100 (e.g., polycarbonate 200 of the first embodiment or polycarbonate 202 of the second embodiment or both), or both. Further, example bacteria can include, but are not limited to, A. baumannii, E. coli, K. pneumoniae, and the like, or combinations thereof.

At 904, the method 900 can include increasing ROS production in the microorganism with one or more anti-rheumatic drugs. For example, the one or more polycarbonate polymers can enable or enhance thioredoxin reductase inhibitor activity with the one or more anti-rheumatic drugs, thereby allowing the one or more anti-rheumatic drugs to exhibit enhanced antibacterial activity. For example, auranofin can exhibit antibacterial activity against gram-negative bacteria.

Figure 10 shows a flow diagram of a non-limiting example method 1000 of one or more combination therapies including one or more poly(guanidinium carbonate) polymers and an anti-rheumatic drug according to one or more embodiments described herein. Repetitive descriptions of similar elements used in other embodiments described herein are omitted for the purposes of brevity.

The method 1000 can include, at 1002, treating a bacterial infection via a combination therapy including one or more anti-rheumatic drugs and one or more polycarbonate polymers functionalized with one or more guanidinium functional groups, where the one or more polycarbonate polymers can enhance the anti-bacterial activity of the one or more anti-rheumatic drugs. For example, the one or more anti-bacterial drugs can be auranofin, or the one or more polycarbonate polymers can be characterized by chemical structure 100 (e.g., polycarbonate 200 of the first embodiment or polycarbonate 202 of the second embodiment or both), or both. Further, example bacteria can include, but are not limited to, A. baumannii, E. coli, K. pneumoniae, and the like, or combinations thereof.

At 1004, the method 1000 includes translocating one or more polycarbonate polymers through the cell membrane 304. For example, the translocation at 1004 can be accomplished according to the translocation mechanism 300 described herein. By way of example, the cell membrane 304 can be a cell membrane of a microorganism targeted for the antimicrobial activity of one or more antirheumatic drugs.

At 1006, the method 1000 can include precipitating one or more microbial cytosol members through an interaction between the one or more cytosol members and the one or more polycarbonate polymers. For example, following translocation 1004, the one or more polycarbonate polymers can bind or precipitate or both the one or more cytosol members. Exemplary cytosol members can include, but are not limited to, proteins, enzymes, or genes, or combinations thereof. In various embodiments, the one or more cytosol members targeted by the interaction at 1006 can be cytosol members that would otherwise inhibit one or more antimicrobial functions of one or more antirheumatic drugs.

At step 1008, the method 1000 can include increasing ROS production in the microorganism with one or more anti-rheumatic drugs. For example, the one or more anti-rheumatic drugs can inhibit thioredoxin reductase in the microorganism. In various embodiments, increasing ROS production at 1008 can be enabled by translocation at 1004 or interaction at 1006, or both, effected at least in part by one or more polycarbonate polymers. Thus, the activity of the one or more polycarbonate polymers can have a synergistic effect with the activity of the one or more anti-rheumatic drugs, thereby facilitating improved antimicrobial activity.

Throughout this disclosure, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". That is, unless otherwise stated or clear from the context, "X uses A or B" is intended to mean any ordinary inclusive exchange. That is, if X uses A; X uses B; or X uses A and B, then "X uses A or B" is satisfied under any of the above examples. Furthermore, the articles "a" and "an" as used in the subject specification and accompanying drawings should generally be construed to mean "one or more" unless otherwise specified or clear from the context to refer to a single form. As used herein, the terms "example" or "exemplary" or both are used to mean serving as an example, example, or illustration. For the avoidance of doubt, the subject matter described herein is not limited by such examples. Additionally, any feature or design described herein as "embodiment" or "exemplary" or both is not necessarily to be construed as preferred or advantageous over other features or designs, and is not meant to exclude equivalent exemplary structures and techniques known to those skilled in the art.

Of course, for purposes of describing this disclosure, it is not possible to describe every conceivable combination of components, products, or methods, but one skilled in the art can recognize that many further combinations and permutations of the present disclosure are possible. Furthermore, as used in the detailed description, claims, appendices, and drawings, "including," "having," "owning," and the like are intended to be inclusive in the manner of the term "comprises," such that "comprises" is interpreted when used as a transitional term in the claims. The description of various embodiments is presented for illustrative purposes and is not intended to be exclusive or limiting of the disclosed embodiments. Many modifications and variations will be obvious to those skilled in the art without departing from the scope of the disclosed embodiments. The terms used in this specification have been selected to best explain the principles of the embodiments, practical applications or technical improvements beyond those found in the marketplace, or to enable those skilled in the art to understand the embodiments disclosed herein.

Claims (14)

1. A chemical composition comprising:
A polycarbonate polymer functionalized with guanidinium functional groups; and
an antirheumatic drug exhibiting thioredoxin reductase inhibitory activity , wherein the polycarbonate polymer enhances the antibacterial activity of the antirheumatic drug;
Chemical composition. 1. A chemical composition comprising:
A polycarbonate polymer functionalized with guanidinium functional groups; and
A chemical composition comprising an antirheumatic drug, said antirheumatic drug being 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-κS ¹ )(triethylphosphoranylidene)gold , and said polycarbonate polymer enhancing the antibacterial activity of said antirheumatic drug . 3. The chemical composition of claim 1 or 2, wherein the antibacterial activity inhibits gram-negative bacteria. The chemical composition of any one of claims 1 to 3, wherein the polycarbonate polymer enhances the antimicrobial activity by translocation across cell membranes and interaction with cytosolic members of target microorganisms. The chemical composition of claim 4, wherein the cytosolic member is selected from the group consisting of a protein, an enzyme, and a gene. The chemical composition of claim 4, wherein the antimicrobial activity comprises enhancing the production of reactive oxygen species in the target microorganism by the antirheumatic drug. The polycarbonate polymer has the formula:
having a structure characterized by
"R ¹ " corresponds to a first functional group selected from a first group consisting of a biotin group, a sugar group, a first alkyl group, and a first aryl group;
"R ² " corresponds to a second functional group selected from a second group selected from hydrogen, a second alkyl group, and a second aryl group;
"X" corresponds to a spacer structure selected from a third group consisting of a third alkyl group and a third aryl group;
"n" corresponds to an integer greater than or equal to 1 and less than or equal to 1000;
The chemical composition according to any one of claims 1 to 6 . A method for enhancing antibacterial activity (excluding methods for treating humans) comprising contacting a microorganism with a chemical composition comprising a polycarbonate polymer functionalized with guanidinium functional groups and an antirheumatic drug exhibiting thioredoxin reductase inhibitor activity . A method for enhancing antimicrobial activity (excluding methods for treating humans) comprising contacting a microorganism with a chemical composition comprising a polycarbonate polymer functionalized with guanidinium functional groups and an antirheumatic drug, said antirheumatic drug being 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-κS ¹ )(triethylphosphoranylidene)gold. 10. The method of claim 8 or 9, wherein improving the antibacterial activity of the antirheumatic drug comprises translocating the polycarbonate polymer across a cell membrane and interacting the polycarbonate polymer with a cytosolic member of the cell membrane of the microorganism targeted for the antibacterial activity, the cytosolic member being selected from the group consisting of a protein, an enzyme and a gene. The method of claim 10, wherein the antimicrobial activity comprises enhancing the production of reactive oxygen species in the microorganism by the antirheumatic drug. The method of any one of claims 8 to 11, wherein the antibacterial activity inhibits gram-negative bacteria. The method according to any one of claims 8 to 12 , wherein the combination therapy alleviates the onset of resistance to the antibacterial activity by the microorganisms targeted by the antirheumatic drug. The polycarbonate polymer has the formula:
and having a structure characterized by
"R ¹ " corresponds to a first functional group selected from a first group consisting of a biotin group, a sugar group, a first alkyl group, and a first aryl group;
"R ² " corresponds to a second functional group selected from a second group selected from hydrogen, a second alkyl group, and a second aryl group;
"X" corresponds to a spacer structure selected from a third group consisting of a third alkyl group and a third aryl group;
"n" corresponds to an integer greater than or equal to 1 and less than or equal to 1000,
The method according to any one of claims 8 to 13 .