Antimicrobial resistance is a dynamic narrative of evolving pathogens and pharmaceutical interventions. Each new antibiotic iteration triggers a dance of resistance mechanisms in targeted microbes, necessitating ongoing innovation in drug development.
In a recent study published in npj Antimicrobials and Resistance, researchers from Sanford Burnham Prebys and Roche Pharma Research investigated the distinctly different resistance mechanisms employed by Escherichia coli and Acinetobacter baumannii against antibiotics.
“This work was conceived as a comparative study of the mechanisms and dynamics of resistance acquisition for two drugs and two bugs,” said senior author Andrei Osterman. “Comparing mutational landscapes triggered by the same drug in two distinct bugs allows us to deduce both shared and unique evolutionary trajectories toward resistance. A comparison of two drugs in the same bug reveals shared and unique mechanistic features of fundamental and translational importance, from drug discovery to rational optimization of treatment regimens.”
The study utilized combined experimental evolution in a continuous culturing device (morbidostat) with whole genome sequencing of evolving cultures to track how E. coli and A. baumannii acquired drug resistance against a pair of antibiotics that inhibit DNA gyrase, an essential enzyme in bacteria. Notably, bacteria resistant to ciprofloxacin remained susceptible to GP6, but resistance to GP6 conferred cross-resistance to ciprofloxacin. This highlights shared and distinct resistance mechanisms in these pathogens.
“Bacteria acquire resistance as a result of random mutational events that happen in the DNA replication as uncorrected ‘typos’,” said Osterman. “These spontaneously emerge in a handful of drug-resistant variants/strains out of godzillions of neutral mutations) under selective pressure.”
Osterman said the work advances progress toward developing “resistibility profiles” of established and novel antimicrobial drugs, which would help set forth “boundaries for possible combinational treatment, including clinically relevant multidrug resistant strains. Our acquired knowledge provides crucial guidelines for all these translational activities.”