Resistance Evolution of Common Human Pathogens Reveals Conserved Resistance Mechanisms in Select Drugs

Description

Abstract
The ESKAPE pathogens (E. faecium, S. aureus, A. baumannii, P. aeruginosa, and E. cloacae) are a leading cause of many nosocomial infections and are often resistant to a wide variety of antimicrobials. Despite their medical importance, very little is known about the evolutionary trajectories that lead to antibiotic resistance for these organisms when exposed to similar antibiotic selection pressure and conditions. We performed a systematic resistance evolution study under uniform growth conditions using ve clinically relevant antibiotics with diverse modes of action with this pathogen group. Following resistance evolution, we investigated the collateral effects arising from single drug resistance, assessed the cost of resistance evolution, and investigated the molecular mechanisms behind the observed phenotypes. Resistance evolution frequently led to high levels of resistance in most species and drugs. A. baumannii isolates of gentamycin evolved populations achieved a 1000-fold improvement in their resistance relative to their ancestral wild type. E. faecium was consistently found to be the least evolved species. Resistance evolution to one antibiotic frequently resulted in high levels of cross-resistance. We observed a high degree of agreement among the different species with three universal cross resistance relationship being found. Instances of collateral sensitivity were notably fewer and nearly all observed instances involved gentamycin sensitivity. Fitness costs associated with resistance evolution varied by drug and were conserved across the species. Resistance evolution toward gentamycin was found to have the largest fitness cost. The observed mutations could be divided into two groups - those with diverse mechanisms of resistance and those with conserved responses. Drugs that yielded diverse genomic response had mutations in multiple gene categories while antibiotics that elicited a conserved response contained mutations in a single gene or select group of genes across all species. We observed that drugs that triggered a conserved genomic response were evolved to quickly and at higher levels. Genomic evolutionary trajectory did not appear to influence cross-resistance patterns. Together, our results provide insight into the evolutionary trajectories and resistance mechanisms undertaken by the ESKAPE species during long-term antibiotic exposure. Additionally these results highlight the importance of broadening resistance evolution studies to include a broader range of organisms.

Period	22 Jun 2019
Event title	ASM Microbe 2019
Event type	Conference
Location	San Francisco, United States