Suppressive Drug Combinations and Their Potential to Combat Antibiotic Resistance

Overview

Journal J Antibiot (Tokyo)

Specialties Infectious Diseases
Pharmacology

Date 2017 Sep 7

PMID 28874848

Citations 38

Authors

Nina Singh

Pamela J Yeh

Affiliations

Soon will be listed here.

Abstract

Antibiotic effectiveness often changes when two or more such drugs are administered simultaneously and unearthing antibiotic combinations with enhanced efficacy (synergy) has been a longstanding clinical goal. However, antibiotic resistance, which undermines individual drugs, threatens such combined treatments. Remarkably, it has emerged that antibiotic combinations whose combined effect is lower than that of at least one of the individual drugs can slow or even reverse the evolution of resistance. We synthesize and review studies of such so-called 'suppressive interactions' in the literature. We examine why these interactions have been largely disregarded in the past, the strategies used to identify them, their mechanistic basis, demonstrations of their potential to reverse the evolution of resistance and arguments for and against using them in clinical treatment. We suggest future directions for research on these interactions, aiming to expand the basic body of knowledge on suppression and to determine the applicability of suppressive interactions in the clinic.

Citing Articles

Drug combinations targeting antibiotic resistance.

Bognar B, Spohn R, Lazar V NPJ Antimicrob Resist. 2025; 2(1):29.

PMID: 39843924 PMC: 11721080. DOI: 10.1038/s44259-024-00047-2.

Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice.

Ishak A, Mazonakis N, Spernovasilis N, Akinosoglou K, Tsioutis C J Antimicrob Chemother. 2024; 80(1):1-17.

PMID: 39471409 PMC: 11695898. DOI: 10.1093/jac/dkae380.

"Stop, Little Pot" as the Motto of Suppressive Management of Various Microbial Consortia.

Efremenko E, Stepanov N, Senko O, Maslova O, Lyagin I, Domnin M Microorganisms. 2024; 12(8).

PMID: 39203492 PMC: 11356704. DOI: 10.3390/microorganisms12081650.

Exploring antimicrobial interactions between metal ions and quaternary ammonium compounds toward synergistic metallo-antimicrobial formulations.

Lekhan A, Turner R Microbiol Spectr. 2024; 12(10):e0104724.

PMID: 39162494 PMC: 11448152. DOI: 10.1128/spectrum.01047-24.

Evolutionary druggability for low-dimensional fitness landscapes toward new metrics for antimicrobial applications.

Guerrero R, Dorji T, Harris R, Shoulders M, Ogbunugafor C Elife. 2024; 12.

PMID: 38833384 PMC: 11149929. DOI: 10.7554/eLife.88480.

References

Balaban N, Merrin J, Chait R, Kowalik L, Leibler S . Bacterial persistence as a phenotypic switch. Science. 2004; 305(5690):1622-5. DOI: 10.1126/science.1099390. View

Cottarel G, Wierzbowski J . Combination drugs, an emerging option for antibacterial therapy. Trends Biotechnol. 2007; 25(12):547-55. DOI: 10.1016/j.tibtech.2007.09.004. View

Yeh P, Tschumi A, Kishony R . Functional classification of drugs by properties of their pairwise interactions. Nat Genet. 2006; 38(4):489-94. DOI: 10.1038/ng1755. View

Nguyen C, Zhou A, Khan A, Miller J, Yeh P . Pairwise antibiotic interactions in Escherichia coli: triclosan, rifampicin and aztreonam with nine other classes of antibiotics. J Antibiot (Tokyo). 2016; 69(11):791-797. DOI: 10.1038/ja.2016.26. View

Ali B . Agents ameliorating or augmenting experimental gentamicin nephrotoxicity: some recent research. Food Chem Toxicol. 2003; 41(11):1447-52. DOI: 10.1016/s0278-6915(03)00186-8. View

Beppler C, Tekin E, White C, Mao Z, Miller J, Damoiseaux R . When more is less: Emergent suppressive interactions in three-drug combinations. BMC Microbiol. 2017; 17(1):107. PMC: 5420147. DOI: 10.1186/s12866-017-1017-3. View

Bretscher M, Althaus C, Muller V, Bonhoeffer S . Recombination in HIV and the evolution of drug resistance: for better or for worse?. Bioessays. 2004; 26(2):180-8. DOI: 10.1002/bies.10386. View

Singer R, Ward M, Maldonado G . Can landscape ecology untangle the complexity of antibiotic resistance?. Nat Rev Microbiol. 2006; 4(12):943-52. DOI: 10.1038/nrmicro1553. View

SMITH V, Holt R . Resource competition and within-host disease dynamics. Trends Ecol Evol. 2011; 11(9):386-9. DOI: 10.1016/0169-5347(96)20067-9. View

10.

Taubes G . The bacteria fight back. Science. 2008; 321(5887):356-61. DOI: 10.1126/science.321.5887.356. View

11.

Ramon-Garcia S, Ng C, Anderson H, Chao J, Zheng X, Pfeifer T . Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen. Antimicrob Agents Chemother. 2011; 55(8):3861-9. PMC: 3147639. DOI: 10.1128/AAC.00474-11. View

12.

Yeh P, Kishony R . Networks from drug-drug surfaces. Mol Syst Biol. 2007; 3:85. PMC: 1828754. DOI: 10.1038/msb4100133. View

13.

LEPPER M, DOWLING H . Treatment of pneumococcic meningitis with penicillin compared with penicillin plus aureomycin; studies including observations on an apparent antagonism between penicillin and aureomycin. AMA Arch Intern Med. 1951; 88(4):489-94. DOI: 10.1001/archinte.1951.03810100073006. View

14.

Shafer R, Vuitton D . Highly active antiretroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type 1. Biomed Pharmacother. 1999; 53(2):73-86. DOI: 10.1016/s0753-3322(99)80063-8. View

15.

Chait R, Shrestha S, Shah A, Michel J, Kishony R . A differential drug screen for compounds that select against antibiotic resistance. PLoS One. 2011; 5(12):e15179. PMC: 2999542. DOI: 10.1371/journal.pone.0015179. View

16.

Mitosch K, Bollenbach T . Bacterial responses to antibiotics and their combinations. Environ Microbiol Rep. 2015; 6(6):545-57. DOI: 10.1111/1758-2229.12190. View

17.

Haaber J, Friberg C, McCreary M, Lin R, Cohen S, Ingmer H . Reversible antibiotic tolerance induced in Staphylococcus aureus by concurrent drug exposure. mBio. 2015; 6(1). PMC: 4313918. DOI: 10.1128/mBio.02268-14. View

18.

LOEWE S . The problem of synergism and antagonism of combined drugs. Arzneimittelforschung. 1953; 3(6):285-90. View

19.

Stone G, Zhang Q, Castillo R, Doppalapudi V, Bueno A, Lee J . Mechanism of action of NB2001 and NB2030, novel antibacterial agents activated by beta-lactamases. Antimicrob Agents Chemother. 2004; 48(2):477-83. PMC: 321519. DOI: 10.1128/AAC.48.2.477-483.2004. View

20.

Bozic I, Reiter J, Allen B, Antal T, Chatterjee K, Shah P . Evolutionary dynamics of cancer in response to targeted combination therapy. Elife. 2013; 2:e00747. PMC: 3691570. DOI: 10.7554/eLife.00747. View