Drugs That Thwart Antibiotic Resistance

Abstract

Antibiotics are often credited with being one of the major forces behind the expansion of human life expectancy in the past 60 years. Yet at the root of this advancement lies its potential undoing: using antibiotics promotes the emergence and spread of resistant strains, reducing the efficacy of the drugs. Now, rising antibiotic resistance threatens to undo much of the progress of modern medicine. To halt the rise of resistance and preserve the activity of antibiotics, we must find ways to neutralize, modulate, or even invert the evolutionary advantage of resistant strains. Chapter 1 reviews three strategies to overcome antibiotic resistance through the sequential or concurrent use of multiple drugs: resistance mechanism inhibitors, synergistic, antagonistic, and suppressive drug interactions, and collateral sensitivity. Collateral sensitivity occurs when a bacterium acquires a mutation or gene that provides resistance to one drug, but makes them more susceptible to others. This new vulnerability can therefore be exploited to select against resistance mechanisms. Chapter 2 describes a screening strategy, based on direct competition between antibiotic resistant and susceptible strains, for identifying compounds that select against antibiotic resistance genes and cassettes. Using this approach we identified two compounds—β-thujaplicin and disulfiram—that select against the TetA tetracycline resistance pump in E. coli. Furthermore, we demonstrate a two-phase treatment paradigm in which β-thujaplicin drives a tetracycline resistant population back to susceptibility, allowing successful second-phase treatment with tetracycline. Chapter 3 examines the consequences of linking two antibiotics—ciprofloxacin and neomycin—into one hybrid compound. We compared the cross-resistance and genotypic profiles of strains evolved in the hybrid to those evolved in mixtures of its two components. We find that the hybrid inhibits bacterial growth through its ciprofloxacin moiety, but prevents resistance through its neomycin moiety by avoiding a common multiple antibiotic resistance pathway. As a result, strains evolved in the hybrid gain less resistance than those evolved in an unlinked mixture. This indicates that linking two drugs can surpass traditional unlinked combination therapy in its ability to prevent resistance. Finally, Chapter 4 discusses the implications of this work and possible directions for future research in treating antibiotic resistance.