Collateral sensitivity of antibiotic-resistant microbes

Abstract

Understanding how evolution of microbial resistance towards a given antibiotic influences susceptibility to other drugs is a challenge of profound importance. By combining laboratory evolution, genome sequencing, and functional analyses, recent works have charted the map of evolutionary trade-offs between antibiotics and have explored the underlying molecular mechanisms. Strikingly, mutations that caused multidrug resistance in bacteria simultaneously enhanced sensitivity to many other unrelated drugs (collateral sensitivity). Here, we explore how this emerging research sheds new light on resistance mechanisms and the way it could be exploited for the development of alternative antimicrobial strategies.

Keywords: antibiotic resistance; collateral sensitivity; cross-resistance; experimental evolution; multidrug resistance.

Figure 1. Charting the maps of antibiotic cross-resistance and collateral sensitivity.

(A) Laboratory evolution experiments are conducted to evolve antibiotic-resistant bacteria in a controlled setting. They involve serial transfer of growing bacterial populations in parallel for hundreds of generations in the presence of an increasing dosage of one of 20–25 antibiotics. (B) Evolved lines are systematically profiled for changes in susceptibilities against a panel of antibiotics – and for genomic and biochemical alterations underlying these phenotypic changes. (C) Based on antibiotic susceptibility measurements, networks of cross-resistance (i.e., increased resistance to one or more agents) and collateral-sensitivity (increased sensitivity to one or more agents) interactions are inferred. The two networks shown here illustrate such evolutionary interactions between 12 antibiotics as determined previously [6,10]. An arrow from one antibiotic to another indicates that adaptation to one increases the resistance (sensitivity) to another. Aminoglycosides dominate the collateral-sensitivity network, with numerous links to other classes of antibiotics. Antibiotic abbreviations are ampicillin (AMP), cefoxitin (FOX), ciprofloxacin (CPR), nalidixic acid (NAL), nitrofurantoin (NIT), kanamycin (KAN), tobramycin (TOB), tetracycline (TET), doxycycline (DOX), chloramphenicol (CHL), erythromycin (ERY), and trimethoprim (TRM). ‘30S’ and ‘50S’ refer to the two main ribosomal subunits. (D) Distribution of the strength of cross-resistance and collateral-sensitivity interactions as determined previously [6,10]. Abbreviation: MIC, minimum inhibitory concentration.

Figure 2. Molecular mechanisms of collateral sensitivity.

(A) Altered membrane potential decreases the uptake of one class of antibiotics while it diminishes the efflux of others. Resistance to aminoglycoside (red dots) can be achieved partly through reduction in the proton motive force (PMF) across the inner membrane of Escherichia coli. As a side effect, the activity of PMF-dependent major efflux pumps is diminished, leading to hypersensitivity to numerous other antibiotics (blue dots) [6]. (B) Resistance mutation causes genome-wide reprogramming of expression with pleiotropic effects. For example, a specific mutation in a gyrase subunit causes resistance to quinolones (gyrase inhibitors). Simultaneously, the same mutation changes susceptibility to numerous other antibiotics by altering DNA supercoiling and thereby global genomic expression [18]. Expression reprogramming can affect various other cellular subsystems modulating antibiotic resistance, including cell-wall thickness and cell-surface charge in an RNA polymerase mutant [38]. (C) Two drugs inhibiting the same enzyme exhibit collateral sensitivity. A resistance mutation alters the structure of the enzyme in such a way that it becomes resistant to one inhibitor while exhibiting hypersensitivity to the other.

Figure 3. Applying collateral sensitivity to combat resistance.

(A) Simultaneous administration or rapid cycling of a collateral-sensitive antibiotic pair decelerates resistance evolution by constraining the set of available mutational trajectories. (B) Two antibiotics (1,2), showing reciprocal collateral sensitivity, are administered in an alternating fashion. Prolonged treatment with antibiotic 1 selects for variants that have an increased resistance to 1 (blue) and an increased susceptibility to 2. Switching to antibiotic treatment 2 eradicates these variants and selects for mutations that increase susceptibility to 1 (red), hence enabling 1 to be reused. Abbreviation: WT, wild type.