High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance
Open accessAbstract
Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The overlap2 method applied to a compound library enriched for FDA-approved compounds against C. neoformans predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy.
“For example, the overlap2 method was applied to a compound library enriched for FDA-approved compounds against C. neoformans116–119 and successfully predicted that the anticholinergic drug dicyclomine HCl with fluconazole would serve as a potent anti-cryptococcal combination therapy.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [117]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products.
Datsenko, K., & Wanner, B. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.120163297 · Cited by 15,902 · see citing works
Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock
Dellinger, R. P., Levy, M. M., Rhodes, A., Annane, D., Gerlach, H., Opal, S. M., Sevransky, J. E., Sprung, C. L., Douglas, I. S., Jaeschke, R., et al. (2013) · Critical Care Medicine · doi:10.1097/ccm.0b013e31827e83af · Cited by 9,694 · see citing works
Dellinger, R. P., Levy, M. M., Rhodes, A., Annane, D., Gerlach, H., Opal, S. M., Sevransky, J., Sprung, C. L., Douglas, I. S., Jaeschke, R., et al. (2013) · Intensive Care Medicine · doi:10.1007/s00134-012-2769-8 · Cited by 7,282 · see citing works
Intravenous Fluids and Acute Kidney Injury
Ding, X., Cheng, Z., & Qian, Q. (2017) · Blood Purification · doi:10.1159/000452702 · Cited by 6,866 · see citing works
Antibiotic resistance threats in the United States, 2019
(U.S.), C. F. D. C. A. P. (2019) · doi:10.15620/cdc:82532 · Cited by 5,782 · see citing works
Mutations of bacteria from virus sensitivity to virus resistance
Luria, S. E., & Delbrück, M. (1943) · Genetics · doi:10.1093/genetics/28.6.491 · Cited by 3,894 · see citing works
Multi-target therapeutics: when the whole is greater than the sum of the parts
Zimmermann, G. R., Lehár, J., & Keith, C. T. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2006.11.008 · Cited by 1,105 · see citing works
The Antimicrobial Resistance Crisis: Causes, Consequences, and Management
Michael, C. A., Dominey‐Howes, D., & Labbate, M. (2014) · Frontiers in Public Health · doi:10.3389/fpubh.2014.00145 · Cited by 978 · see citing works
Mechanisms of drug combinations: interaction and network perspectives
Jia, J., Zhu, F., Ma, X., Cao, Z., Li, Y. X., & Chen, Y. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2683 · Cited by 975 · see citing works
Combination Therapy for Treatment of Infections with Gram-Negative Bacteria
Tamma, P. D., Cosgrove, S. E., & Maragakis, L. L. (2012) · Clinical Microbiology Reviews · doi:10.1128/cmr.05041-11 · Cited by 837 · see citing works
Phenotypic Landscape of a Bacterial Cell
Nichols, R. J., Sen, Ś., Choo, Y. J., Beltrão, P., Zietek, M., Chaba, R., Lee, S., Kazmierczak, K. M., Lee, K. J., Wong, A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.11.052 · Cited by 702 · see citing works
Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches
Roemer, T., & Krysan, D. J. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a019703 · Cited by 593 · see citing works
Breeding latitude drives individual schedules in a trans-hemispheric migrant bird
Conklin, J. R., Battley, P. F., Potter, M. A., & Fox, J. W. (2010) · Nature Communications · doi:10.1038/ncomms1072 · Cited by 583 · see citing works
Mitomycin C: small, fast and deadly (but very selective)
Tomasz, M. (1995) · Chemistry & Biology · doi:10.1016/1074-5521(95)90120-5 · Cited by 583 · see citing works
Chemical genetics of Plasmodium falciparum
Guiguemde, W. A., Shelat, A. A., Bouck, D. C., Duffy, S., Crowther, G. J., Davis, P. H., Smithson, D. C., Connelly, M., Clark, J. A., Zhu, F., et al. (2010) · Nature · doi:10.1038/nature09099 · Cited by 561 · see citing works
Applied therapeutics; the clinical use of drugs
(1990) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(90)90630-5 · Cited by 401 · see citing works
Hall, B. M., Ma, C.-X., Liang, P., & Singh, K. K. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp253 · Cited by 375 · see citing works
Lindgren, P. K., Karlsson, A., & Hughes, D. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.10.3222-3232.2003 · Cited by 351 · see citing works
Drug interactions and the evolution of antibiotic resistance
Yeh, P. J., Hegreness, M. J., Aiden, A. P., & Kishony, R. (2009) · Nature Reviews Microbiology · doi:10.1038/nrmicro2133 · Cited by 350 · see citing works
Meletiadis, J., Pournaras, S., Roilides, E., & Walsh, T. J. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00999-09 · Cited by 331 · see citing works
Systematic exploration of synergistic drug pairs
Cokol, M., Chua, H. N., Tasan, M., Mutlu, B., Weinstein, Z., Suzuki, Y., Nergiz, M. E., Costanzo, M., Baryshnikova, A., Giaever, G. N., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.71 · Cited by 308 · see citing works
Inducible SOS Response System of DNA Repair and Mutagenesis in Escherichia coli
Janion, C. (2008) · International Journal of Biological Sciences · doi:10.7150/ijbs.4.338 · Cited by 303 · see citing works
Accelerated evolution of resistance in multidrug environments
Hegreness, M., Shoresh, N., Damian, D., Hartl, D., & Kishony, R. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805965105 · Cited by 300 · see citing works
Pethe, K., de Sequeira, P. C., Agarwalla, S., Rhee, K. Y., Kuhen, K., Phong, W. Y., Patel, V., Beer, D., Walker, J. R., Duraiswamy, J., et al. (2010) · Nature Communications · doi:10.1038/ncomms1060 · Cited by 292 · see citing works
Drug repurposing: far beyond new targets for old drugs
Oprea, T. I., & Mestres, J. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9390-1 · Cited by 285 · see citing works
Nucleosides and Nucleotides as Antitumor and Antiviral Agents
Chu, C. K., & Baker, D. C. (1993) · Springer eBooks · doi:10.1007/978-1-4615-2824-1 · Cited by 283 · see citing works
Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures
Spear, E. D., & Kaiser, C. A. (2013) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 266 · see citing works
The interaction between coumarin drugs and DNA gyrase
Maxwell, A. (1993) · Molecular Microbiology · doi:10.1111/j.1365-2958.1993.tb01728.x · Cited by 263 · see citing works
Protein Binding: Do We Ever Learn?
Zeitlinger, M. A., Derendorf, H., Mouton, J. W., Cars, O., Craig, W. A., Andes, D. R., & Theuretzbacher, U. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01433-10 · Cited by 249 · see citing works
Applied Therapeutics. The Clinical Use of Drugs
Kamath, B. L. (1990) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600790320 · Cited by 241 · see citing works
Bacterial methionine biosynthesis
Ferla, M. P., & Patrick, W. M. (2014) · Microbiology · doi:10.1099/mic.0.077826-0 · Cited by 241 · see citing works
Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures
Lee, A. Y., St.Onge, R. P., Proctor, M. J., Wallace, I. M., Nile, A. H., Spagnuolo, P. A., Jitkova, Y., Gronda, M., Wu, Y., Kim, M. K., et al. (2014) · Science · doi:10.1126/science.1250217 · Cited by 241 · see citing works
Synergy assessed by checkerboard a critical analysis
Hsieh, M. H., Yu, C. M., Yu, V. L., & Chow, J. W. (1993) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/0732-8893(93)90087-n · Cited by 229 · see citing works
What is synergy? The Saariselkä agreement revisited
Tang, J. P., Wennerberg, K., & Aittokallio, T. A. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00181 · Cited by 223 · see citing works
Metal limitation and toxicity at the interface between host and pathogen
Becker, K. W., & Skaar, E. P. (2014) · FEMS Microbiology Reviews · doi:10.1111/1574-6976.12087 · Cited by 223 · see citing works
Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance
Coleman, M. D. (1993) · British Journal of Dermatology · doi:10.1111/j.1365-2133.1993.tb00476.x · Cited by 215 · see citing works
Stehr, C. M., Linbo, T. L., Incardona, J. P., & Scholz, N. L. (2006) · Toxicological Sciences · doi:10.1093/toxsci/kfj185 · Cited by 212 · see citing works
Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coli
Davies, B. W., Kohanski, M. A., Simmons, L. A., Winkler, J. A., Collins, J. J., & Walker, G. C. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.11.024 · Cited by 203 · see citing works
Schwarzmüller, T., Ma, B., Hiller, E., Istel, F., Tscherner, M., Brunke, S., Ames, L., Firon, A., Green, B., Cabral, V., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004211 · Cited by 191 · see citing works
Cross‐species discovery of syncretic drug combinations that potentiate the antifungal fluconazole
Spitzer, M., Griffiths, E., Blakely, K. M., Wildenhain, J., Ejim, L., Rossi, L., De Pascale, G., Curak, J., Brown, E., Tyers, M., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.31 · Cited by 183 · see citing works
Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria
Tängdén, T. (2014) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2014.899279 · Cited by 182 · see citing works
Antifungal Drug Discovery: Something Old and Something New
Butts, A., & Krysan, D. J. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002870 · Cited by 182 · see citing works
Walton, E. M., Cronan, M. R., Beerman, R. W., & Tobin, D. M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0138949 · Cited by 168 · see citing works
Optimal Drug Synergy in Antimicrobial Treatments
Torella, J. P., Chait, R., & Kishony, R. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000796 · Cited by 164 · see citing works
Antibacterial activity and mechanism of action of 3'-azido-3'-deoxythymidine (BW A509U)
Elwell, L. P., Ferone, R., Freeman, G. A., Fyfe, J. A., Hill, J. A., Ray, P. H., Richards, C. A., Singer, S. C., Knick, V. B., & Rideout, J. L. (1987) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.31.2.274 · Cited by 161 · see citing works
Systems-level antimicrobial drug and drug synergy discovery
Roemer, T., & Boone, C. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1205 · Cited by 159 · see citing works
Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections
Rangel-Vega, A., Bernstein, L., Mandujano-Tinoco, E., García-Contreras, S. J., & García-Contreras, R. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00282 · Cited by 158 · see citing works
Spontaneous Mutations That Confer Antibiotic Resistance in Helicobacter pylori
Wang, G., Wilson, T. J., Jiang, Q. L., & Taylor, D. E. (2001) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.45.3.727-733.2001 · Cited by 149 · see citing works
Menon, N. K., Robbins, J., Peck, H. D., Chatelus, C. Y., Choi, E. S., & Przybyla, A. (1990) · Journal of Bacteriology · doi:10.1128/jb.172.4.1969-1977.1990 · Cited by 140 · see citing works
The use of in vivo zebrafish assays in drug toxicity screening
Eimon, P. M., & Rubinstein, A. L. (2009) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250902882128 · Cited by 135 · see citing works
Brothers, K. M., Newman, Z. R., & Wheeler, R. T. (2011) · Eukaryotic Cell · doi:10.1128/ec.05005-11 · Cited by 134 · see citing works
Cruz, M. C., Poeta, M. D., Wang, P., Wenger, R. M., Zenke, G., Quesniaux, V. F. J., Movva, N. R., Perfect, J. R., Cardenas, M. E., & Heitman, J. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.1.143-149.2000 · Cited by 129 · see citing works
Prediction of Synergism from Chemical-Genetic Interactions by Machine Learning
Wildenhain, J., Spitzer, M., Dolma, S., Jarvik, N., White, R., Roy, M. M., Griffiths, E., Bellows, D. S., Wright, G. D., & Tyers, M. (2015) · Cell Systems · doi:10.1016/j.cels.2015.12.003 · Cited by 122 · see citing works
Neuhard, J., & Thomassen, E. (1976) · Journal of Bacteriology · doi:10.1128/jb.126.2.999-1001.1976 · Cited by 120 · see citing works
Chemogenomics and orthology‐based design of antibiotic combination therapies
Chandrasekaran, S., Çakmak, M. Ç., Sahin, N., Yılancıoğlu, K., Kazan, H., Collins, J. J., & Cokol, M. (2016) · Molecular Systems Biology · doi:10.15252/msb.20156777 · Cited by 117 · see citing works
Current concepts in combination antibiotic therapy for critically ill patients
Baronia, A. K., & Ahmed, A. (2014) · Indian Journal of Critical Care Medicine · doi:10.4103/0972-5229.132495 · Cited by 116 · see citing works
Diezmann, S., Michaut, M., Shapiro, R. S., Bader, G. D., & Cowen, L. E. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002562 · Cited by 112 · see citing works
The Gene for Nucleoside Diphosphate Kinase Functions as a Mutator Gene inEscherichia coli
Lu, Q., Zhang, X., Almaula, N., Mathews, C. K., & Inouye, M. (1995) · Journal of Molecular Biology · doi:10.1006/jmbi.1995.0620 · Cited by 110 · see citing works
Bacterial protein networks: properties and functions
Typas, A., & Sourjik, V. (2015) · Nature Reviews Microbiology · doi:10.1038/nrmicro3508 · Cited by 108 · see citing works
Zebrafish: A See-Through Host and a Fluorescent Toolbox to Probe Host–Pathogen Interaction
Tobin, D. M., May, R. C., & Wheeler, R. T. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002349 · Cited by 98 · see citing works
Crowley, D. J., & Hanawalt, P. C. (1998) · Journal of Bacteriology · doi:10.1128/jb.180.13.3345-3352.1998 · Cited by 96 · see citing works
In vivo zebrafish assays for analyzing drug toxicity
Raldúa, D., & Piña, B. (2014) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2014.896339 · Cited by 87 · see citing works
Wiles, T. J., Bower, J. M., Redd, M. J., & Mulvey, M. A. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000697 · Cited by 86 · see citing works
Self-citationUsing a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages
Fuentes-Hernández, A., Plucain, J., Gori, F., Peña‐Miller, R., Reding, C., Jansen, G., Hinrich Schulenburg, Y., Gudelj, I., & Beardmore, R. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002104 · Cited by 84 · see citing works
Unraveling the Biology of a Fungal Meningitis Pathogen Using Chemical Genetics
Brown, J. C. S., Nelson, J., VanderSluis, B., Deshpande, R., Butts, A., Kagan, S., Polacheck, I., Krysan, D. J., Myers, C. L., & Madhani, H. D. (2014) · Cell · doi:10.1016/j.cell.2014.10.044 · Cited by 84 · see citing works
Self-citationSharples, G. J., & Lloyd, R. G. (1991) · Journal of Bacteriology · doi:10.1128/jb.173.23.7711-7715.1991 · Cited by 83 · see citing works
Hama, H., Almaula, N., Lerner, C. G., Inouye, S., & Inouye, M. (1991) · Gene · doi:10.1016/0378-1119(91)90510-i · Cited by 82 · see citing works
Nucleoside diphosphate kinase from Escherichia coli
Almaula, N., Lu, Q., Delgado, J., Belkin, S., & Inouye, M. (1995) · Journal of Bacteriology · doi:10.1128/jb.177.9.2524-2529.1995 · Cited by 82 · see citing works
Xu, D., Sillaots, S., Davison, J., Hu, W., Jiang, B., Kauffman, S., Martel, N., Ocampo, P., Oh, C., Trosok, S., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.019877 · Cited by 79 · see citing works
Robbins, N., Spitzer, M., Yu, T., Cerone, R. P., Averette, A. K., Bahn, Y.-S., Heitman, J., Sheppard, D. C., Tyers, M., & Wright, G. D. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.018 · Cited by 78 · see citing works
Tenor, J. L., Oehlers, S. H., Yang, J. L., Tobin, D. M., & Perfect, J. R. (2015) · mBio · doi:10.1128/mbio.01425-15 · Cited by 78 · see citing works
Mechanism of the antimicrobial drug trimethoprim revisited
Quinlivan, E. P., McPartlin, J. M., Weir, D. G., & Scott, J. (2000) · The FASEB Journal · doi:10.1096/fj.99-1037com · Cited by 75 · see citing works
Using Combination Therapy to Thwart Drug Resistance
Hill, J. A., & Cowen, L. E. (2015) · Future Microbiology · doi:10.2217/fmb.15.68 · Cited by 75 · see citing works
Takahagi, M., Iwasaki, H., Nakata, A., & Shinagawa, H. (1991) · Journal of Bacteriology · doi:10.1128/jb.173.18.5747-5753.1991 · Cited by 74 · see citing works
Escherichia coli Genes and Pathways Involved in Surviving Extreme Exposure to Ionizing Radiation
Byrne, R. T., Chen, S. H., Wood, E. A., Cabot, E. L., & Cox, M. M. (2014) · Journal of Bacteriology · doi:10.1128/jb.01589-14 · Cited by 73 · see citing works
Gustafsson, I. (2003) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkg427 · Cited by 71 · see citing works
Zuo, G., Li, Y., Wang, T., Han, J. H., Wang, G.-C., Zhang, Y., & Pan, W. (2011) · Molecules · doi:10.3390/molecules16129819 · Cited by 67 · see citing works
Mutational consequences of dNTP pool imbalances in E. coli
Schaaper, R. M., & Mathews, C. K. (2012) · DNA repair · doi:10.1016/j.dnarep.2012.10.011 · Cited by 65 · see citing works
O’Donovan, G. A., Edlin, G. J., Fuchs, J. A., Neuhard, J., & Thomassen, E. (1971) · Journal of Bacteriology · doi:10.1128/jb.105.2.666-672.1971 · Cited by 62 · see citing works
The Biosynthesis of Folic Acid
Suzuki, Y., & Brown, G. M. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)42745-2 · Cited by 59 · see citing works
Chemotherapeutic Agents for the Treatment of Hepatocellular Carcinoma: Efficacy and Mode of Action
Shaaban, S., Negm, A., Ibrahim, E., & Elrazak, A. A. (2014) · Oncology Reviews · doi:10.4081/oncol.2014.246 · Cited by 58 · see citing works
Combination Antimicrobial Treatment Versus Monotherapy: The Contribution of Meta-analyses
Paul, M., & Leibovici, L. (2009) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2009.01.004 · Cited by 52 · see citing works
Cooper, D. L., & Lovett, S. T. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.11.007 · Cited by 49 · see citing works
Comer, M. M., & Böck, A. (1976) · Journal of Bacteriology · doi:10.1128/jb.127.2.923-933.1976 · Cited by 43 · see citing works
Initial Clinical Experience with Dideoxynucleosides as Single Agents and in Combination Therapy
Yarchoan, R., Pluda, J. M., Perno, C. F., Mitsuya, H., Thomas, R. V., Wyvill, K., & Broder, S. E. (1990) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1990.tb17853.x · Cited by 42 · see citing works
Chemogenomic profiling of Plasmodium falciparum as a tool to aid antimalarial drug discovery
Pradhan, A., Siwo, G., Singh, N. P., Martens, B., Balu, B., Button-Simons, K. A., Tan, A., Zhang, M., Udenze, K., Jiang, R. H. Y., et al. (2015) · Scientific Reports · doi:10.1038/srep15930 · Cited by 42 · see citing works
Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia
Luo, G., Spellberg, B. J., Gebremariam, T., Lee, H., Xiong, Y. Q., French, S. W., Bayer, A. S., & Ibrahim, A. S. (2013) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-013-2023-5 · Cited by 39 · see citing works
Practical guidance for nonoccupational postexposure prophylaxis to prevent HIV infection
Jain, S., & Mayer, K. H. (2014) · AIDS · doi:10.1097/qad.0000000000000301 · Cited by 37 · see citing works
Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides
Mamber, S. W., Brookshire, K. W., & Forenza, S. (1990) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.34.6.1237 · Cited by 35 · see citing works
Barber, A. E., Fleming, B. A., & Mulvey, M. A. (2016) · mSphere · doi:10.1128/msphere.00062-16 · Cited by 33 · see citing works
Self-citationPrevention of Drug Resistance by Combined Drug Treatment of Tuberculosis
Mitchison, D. A. (2012) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-28951-4_6 · Cited by 28 · see citing works
Fluctuation analysis of mutations to nalidixic acid resistance in Escherichia coli.
Boe, L., Tolker-Nielsen, T., Eegholm, K. M., Spliid, H., & Vrang, A. (1994) · Journal of Bacteriology · doi:10.1128/jb.176.10.2781-2787.1994 · Cited by 26 · see citing works
Seier, T., Zilberberg, G., Zeiger, D. M., & Lovett, S. T. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116160109 · Cited by 25 · see citing works
Russell, C. W., & Mulvey, M. A. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005317 · Cited by 25 · see citing works
Self-citationKristich, C. J., Djorić, D., & Little, J. L. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02001-13 · Cited by 23 · see citing works
Antibacterial activity of fluoroquinolones in combination with zidovudine
Lewin, C. S., ALLEN, R. A., & Amyes, S. G. B. (1990) · Journal of Medical Microbiology · doi:10.1099/00222615-33-2-127 · Cited by 19 · see citing works
Donabedian, H., & Andriole, V. T. (1977) · PubMed · Cited by 16 · see citing works
Trimethoprim/Sulfamethoxazole: An Overview
Wormser, G. P., & Keusch, G. T. (1983) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-81890-5_1 · Cited by 12 · see citing works
Uchikubo, Y., Hasegawa, T., Mitani, S., Kim, H.-S., & Wataya, Y. (2002) · Nucleic Acids Symposium Series · doi:10.1093/nass/2.1.245 · Cited by 8 · see citing works
Trimethoprim/sulfonamide: rational combination therapy.
Hitchings, G. H., & Singleton, S. W. (1976) · PubMed · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [88]Gustafsson I, Sjolund M, Torell E, Johannesson M, Engstrand L, Cars O, et al Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage. J Antimicrob Chemother. 2003; 52: 645– 50. doi: 10.1093/jac/dkg427 12972454 · DOI
Cited by
Sorted by citations
Drug combinations: a strategy to extend the life of antibiotics in the 21st century
Tyers, M., & Wright, G. D. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-018-0141-x · Cited by 825 · see citing works
Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds
Proschak, E., Stark, H., & Merk, D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00760 · Cited by 498 · see citing works
Treatment strategies for cryptococcal infection: challenges, advances and future outlook
Iyer, K. R., Revie, N. M., Fu, C., Robbins, N., & Cowen, L. E. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00511-0 · Cited by 363 · see citing works
Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria
Liu, Y., Tong, Z., Shi, J., Li, R., Upton, M., & Wang, Z. (2021) · Theranostics · doi:10.7150/thno.56205 · Cited by 236 · see citing works
Nucleoside Analogues as Antibacterial Agents
Thomson, J. M., & Lamont, I. L. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.00952 · Cited by 177 · see citing works
Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis
Lakemeyer, M., Zhao, W., Mandl, F. A. M., Hammann, P., & Sieber, S. A. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201804971 · Cited by 170 · see citing works
Ayon, N. J. (2023) · Metabolites · doi:10.3390/metabo13050625 · Cited by 156 · see citing works
Metal-Based Nanoparticles as Antimicrobial Agents: A Review
Luo, L., Huang, W., Zhang, J., Yu, Y., & Sun, T. (2024) · ACS Applied Nano Materials · doi:10.1021/acsanm.3c05615 · Cited by 135 · see citing works
Natural Extracts for Antibacterial Applications
Chen, C., Chen, L., Mao, C., Jin, L., Wu, S., Zheng, Y., Cui, Z., Li, Z., Zhang, Y., Zhu, S., et al. (2023) · Small · doi:10.1002/smll.202306553 · Cited by 114 · see citing works
Understanding and overcoming antibiotic resistance
Richardson, L. A. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2003775 · Cited by 99 · see citing works
The future of antibiotics begins with discovering new combinations
Zhu, M., Tse, M. W., Weller, J., Chen, J., & Blainey, P. C. (2021) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14649 · Cited by 84 · see citing works
Phytotherapy as an alternative to conventional antimicrobials: combating microbial resistance
Enioutina, E. Y., Teng, L., Fateeva, T. V., Brown, J. C. S., Job, K. M., Бортникова, В. В., Krepkova, L. V., Gubarev, M. I., & Sherwin, C. M. T. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1371591 · Cited by 78 · see citing works
Self-citationXu, Z., Li, M., Li, Y., Cao, H., Lu, M., Xu, Z., Higuchi, Y., Yamasaki, S., Nishino, K., Woo, P. C. Y., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.006 · Cited by 71 · see citing works
Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections
Wambaugh, M. A., Denham, S. T., Ayala, M., Brammer, B., Stonhill, M. A., & Brown, J. C. (2020) · eLife · doi:10.7554/elife.54160 · Cited by 65 · see citing works
Self-citationLiu, Y., Jia, Y., Yang, K., Li, R., Xiao, X., & Wang, Z. (2020) · Communications Biology · doi:10.1038/s42003-020-0877-5 · Cited by 63 · see citing works
Weldrick, P. J., Iveson, S., Hardman, M. J., & Paunov, V. N. (2019) · Nanoscale · doi:10.1039/c8nr10022e · Cited by 59 · see citing works
Dillon, N. A., Holland, M. M., Tsunemoto, H., Hancock, B., Cornax, I., Pogliano, J., Sakoulas, G., & Nizet, V. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.07.041 · Cited by 47 · see citing works
Progress Report: Antimicrobial Drug Discovery in the Resistance Era
Shinu, P., Mouslem, A. K. A., Nair, A. B., Venugopala, K. N., Attimarad, M., Singh, V. A., Sreeharsha, N., Alotaibi, G., & Deb, P. K. (2022) · Pharmaceuticals · doi:10.3390/ph15040413 · Cited by 45 · see citing works
Ng, S. M. S., Sioson, J. S. P., Yap, J. M., Ng, F. M., Ching, H. S. V., Teo, J. W. P., Jureen, R., Hill, J., & Chia, C. S. B. (2017) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-017-3114-5 · Cited by 44 · see citing works
Synthetic molecular evolution of antimicrobial peptides
Chen, C. H., Bepler, T., Pepper, K., Fu, D., & Lu, T. K. (2022) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2022.102718 · Cited by 43 · see citing works
Habjan, E., Schouten, G. K., Speer, A., van Ulsen, P., & Bitter, W. (2024) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuae011 · Cited by 37 · see citing works
Use of genetic and chemical synthetic lethality as probes of complexity in bacterial cell systems
Klobucar, K., & Brown, E. D. (2017) · FEMS Microbiology Reviews · doi:10.1093/femsre/fux054 · Cited by 29 · see citing works
Chen, H.-L., Liu, C., Li, M., Zhang, H., Xian, M., & Liu, H. (2018) · RSC Advances · doi:10.1039/c8ra01783b · Cited by 28 · see citing works
Mrak, P., Krastel, P., Lukančič, P. P., Tao, J., Pistorius, D., & Moore, C. M. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005314 · Cited by 26 · see citing works
Falagas, M. E., Voulgaris, G. L., Tryfinopoulou, K., Giakkoupi, P., Kyriakidou, M., Vatopoulos, A. C., Coates, A. R. M., & Hu, Y. (2019) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2019.02.021 · Cited by 24 · see citing works
The antimicrobial resistance crisis needs action now
Pariente, N., & Editors, O. B. O. T. P. B. S. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001918 · Cited by 22 · see citing works
A Strategic Target Rescues Trimethoprim Sensitivity in Escherichia coli
Bhosle, A., Datey, A., Chandrasekharan, G., Singh, D., Chakravortty, D., & Chandra, N. R. (2020) · iScience · doi:10.1016/j.isci.2020.100986 · Cited by 21 · see citing works
Hanna, N., Kicka, S., Chiriano, G., Harrison, C. F., Ouertatani-Sakouhi, H., Trofimov, V., Kranjc, A., Nitschke, J., Pagni, M., Cosson, P., et al. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00266 · Cited by 16 · see citing works
Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise
Lakemeyer, M., Zhao, W., Mandl, F. A. M., Hammann, P., & Sieber, S. A. (2018) · Angewandte Chemie · doi:10.1002/ange.201804971 · Cited by 18 · see citing works
Aloni-Grinstein, R., Mamroud, E., & Gal, Y. (2025) · Microorganisms · doi:10.3390/microorganisms13092115 · Cited by 17 · see citing works
Achieving a Predictive Understanding of Antimicrobial Stress Physiology through Systems Biology
Mack, S. G., Turner, R. L., & Dwyer, D. J. (2018) · Trends in Microbiology · doi:10.1016/j.tim.2018.02.004 · Cited by 16 · see citing works
Liu, Q., Zhang, S., Huang, Y., & Jones, J. B. (2019) · Crop Protection · doi:10.1016/j.cropro.2019.02.006 · Cited by 16 · see citing works
Maeda, T., Horinouchi, T., Sakata, N., Sakai, A., & Furusawa, C. (2019) · The Journal of Antibiotics · doi:10.1038/s41429-019-0160-5 · Cited by 15 · see citing works
Chemical biology-whole genome engineering datasets predict new antibacterial combinations
Turner, A. K., Yasir, M., Bastkowski, S., Telatin, A., Page, A. J., Webber, M. A., & Charles, I. G. (2021) · Microbial Genomics · doi:10.1099/mgen.0.000718 · Cited by 13 · see citing works
Better living through chemistry: Addressing emerging antibiotic resistance
Coussens, N. P., Molinaro, A. L., Culbertson, K. J., Peryea, T., Zahoránszky-Köhalmi, G., Hall, M. D., & Daines, D. A. (2018) · Experimental Biology and Medicine · doi:10.1177/1535370218755659 · Cited by 13 · see citing works
DeSarno, A. E., Parcell, B. J., & Coote, P. J. (2020) · Pathogens and Disease · doi:10.1093/femspd/ftaa063 · Cited by 12 · see citing works
Chemical-Chemical Combinations Map Uncharted Interactions in Escherichia coli under Nutrient Stress
Zahed, S. S. E., & Brown, E. D. (2018) · iScience · doi:10.1016/j.isci.2018.03.018 · Cited by 12 · see citing works
The Experimentalist’s Guide to Machine Learning for Small Molecule Design
Lindley, S. E., Lu, Y., & Shukla, D. (2023) · ACS Applied Bio Materials · doi:10.1021/acsabm.3c00054 · Cited by 11 · see citing works
In Vitro and In Vivo Activity of (Trifluoromethyl)pyridines as Anti-Chlamydia trachomatis Agents
Seleem, M. A., Wood, N. A., Brinkworth, A. J., Manam, S., Carabeo, R. A., Murthy, A. K., Ouellette, S. P., & Conda‐Sheridan, M. (2021) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.1c00553 · Cited by 10 · see citing works
Stein, D., Thom, V., & Hubbuch, J. J. (2020) · Biotechnology Progress · doi:10.1002/btpr.3055 · Cited by 9 · see citing works
Tian, P., Li, Q., Guo, M., Zhu, Y.-Z., Zhu, R.-Q., Guo, Y.-Q., Yang, Y., Liu, Y., Yu, L., Li, Y., et al. (2024) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00344-24 · Cited by 8 · see citing works
Carbohydrate-based antibiotics: Opportunities and challenges
Singh, G. S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816675-8.00013-0 · Cited by 8 · see citing works
Xue, J. M., Yi, J., & Zhou, H. H. (2021) · Molecules · doi:10.3390/molecules26102962 · Cited by 7 · see citing works
Levenfors, J. J., Bjerketorp, J., Guss, B., Nord, C. L., Cao, S., Hughes, D., Broberg, A., & Öberg, B. F. (2024) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkae438 · Cited by 6 · see citing works
Synthesis of functionalized sulfonamides as antitubercular agents
Hearn, M. J., Pugh, C. D., & Cynamon, M. H. (2023) · Phosphorus, sulfur, and silicon and the related elements · doi:10.1080/10426507.2023.2196079 · Cited by 6 · see citing works
High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Wambaugh, M. A., & Brown, J. C. S. (2018) · Journal of Visualized Experiments · doi:10.3791/57241 · Cited by 5 · see citing works
Self-citationXu, J., Cai, Y., Jiang, B., Li, X., Jin, H. Y., Liu, W., Kong, Z., Hong, J., Sealy, J. E., Iqbal, M., et al. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.08.165 · Cited by 4 · see citing works
Moreau, K., Surand, J., Dantec, A. L., Mosrin-Huaman, C., Legrand, A., & Rahmouni, A. R. (2018) · The Journal of Antibiotics · doi:10.1038/s41429-017-0007-x · Cited by 4 · see citing works
Xu, J., Li, X., Jiang, B., Feng, X., Wu, J., Cai, Y., Zhang, X., Huang, X., Sealy, J. E., Iqbal, M., et al. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00653 · Cited by 3 · see citing works
Gong, W.-T., Zhao, X.-J., Wang, G.-M., Ma, X., & Huang, J.-A. (2023) · Microbiology Spectrum · doi:10.1128/spectrum.04843-22 · Cited by 2 · see citing works
Transfer learning predicts species-specific drug interactions in emerging pathogensPreprint
Chung, C. H., Chang, D. C., Rhoads, N. M., Shay, M. R., Srinivasan, K., Okezue, M. A., Brunaugh, A. D., & Chandrasekaran, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.04.597386 · Cited by 2 · see citing works
Hijacking anaerobic metabolism to restore antibiotic efficacy in Pseudomonas aeruginosa
Gentry-Lear, Z., Padilla, C. L., & Spero, M. A. (2025) · Applied and Environmental Microbiology · doi:10.1128/aem.01425-25 · Cited by 1 · see citing works
Sinha, A. R., & Goulian, M. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116813 · Cited by 1 · see citing works
Trends in the Use of Proper Methods for Estimating Mutation Rates in Fluctuation Experiments
Devin, G. A., & Couce, A. (2023) · Axioms · doi:10.3390/axioms12121100
A duplexed CRISPRi-based approach to predict synergistic antibiotic targets in Escherichia coliPreprint
Xiong, X., Furseth, H., McCoy, B., Slavic, L., Yuan, X. F., Chen, S., Baughn, A. D., Minato, Y., & Harcombe, W. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.15.594409
Likhachev, I. V., Кафтырева, Л. А., Samoilova, A. A., Краева, Л. А., & Mikhailov, N. V. (2024) · Clinical Microbiology and Antimicrobial Chemotherapy · doi:10.36488/cmac.2024.1.98-103
Wei, X., Wang, W., Arbab, S., Wang, Q., Bai, Y., & Zhang, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-07751-7
Ghazi-Soltani, G., Kebbi‐Beghdadi, C., Adams, S. E., & Greub, G. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.15.682642
Ayala, M., Jakamartana, A., Costa, R. M. D. S., Bednarek, J. M., Moreau, C. T., Cheung, C. K., & Brown, J. C. S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.31.697249
Self-citationTACTIC: A transfer learning framework to predict drug interactions in emerging pathogens
Chung, C. H., Chang, D. C., Rhoads, N. M., Lalitha, P., Rameshkumar, G., Karpagam, R., Vimaladevi, M., Shay, M. R., Srinivasan, K., Okezue, M. A., et al. (2026) · Cell Reports Methods · doi:10.1016/j.crmeth.2026.101513 · Cited by 2 · see citing works
Monreal, A., Ballestero, D., Yus, C., Mattar, I., Mendoza, G., Langa, E., Pino-Otín, M. R., & Arruebo, M. (2026) · Antibiotics · doi:10.3390/antibiotics15080721
Cheung, E. C.-K., Stevens, C., Tate, B., Mulvey, M. A., & Brown, J. C. S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.03.742500
Self-citationAyala, M., Jakamartana, A., Costa, R. M. D. S., Cheung, E. C.-K., Bednarek, J. M., Moreau, C. T., & Brown, J. C. S. (2026) · mSphere · doi:10.1128/msphere.00432-26
Self-citationBindingDB (2021) · UC San Diego · doi:10.7270/q25t3pv2
- Authors
- Wambaugh, M. A., Shakya, V. P. S., Lewis, A. J., Mulvey, M. A., & Brown, J. C. S.
- Affiliations
- University of Utah (US)
- Corresponding author
- Brown, Jessica C. S.
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-06-20
- Volume
- 15
- Issue
- 6
- Pages
- e2001644
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC5478098
- OpenAlex
- W2637550166
- Cited by
- 63
- References
- 100
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 11 · 2017: 4
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Department of Pathology, University of Utah
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- antibiotic resistance, synergistic drug combination, high-throughput screening, trimethoprim, sulfamethizole, zidovudine, nucleotide homeostasis, DNA replication inhibition, Escherichia coli, Klebsiella pneumoniae, urinary tract infection, rational drug design
- MeSH terms
- Animals, Anti-Infective Agents, Urinary, Anti-Bacterial Agents, Bacterial Proteins, Biological Assay, Drug Synergism, Drug Therapy, Combination, Embryo, Nonmammalian, Escherichia coli, Escherichia coli Infections, Folic Acid Antagonists, Klebsiella Infections, Klebsiella pneumoniae, Microbial Sensitivity Tests, Mutation, Pattern Recognition, Automated, Sulfamethizole, Trimethoprim, Zebrafish, Drug Design, Reverse Transcriptase Inhibitors, Computational Biology, Drug Resistance, Multiple, Bacterial, Small Molecule Libraries, High-Throughput Screening Assays, Mutation Rate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
