Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor

Abstract

Beta-lactamase inhibitors are increasingly used to counteract antibiotic resistance mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam antibiotic for the same binding site on the beta-lactamase, thus generating an evolutionary tradeoff: mutations that increase the enzyme's beta-lactamase activity tend to increase also its susceptibility to the inhibitor. Here, we investigate how common and accessible are mutants that escape this adaptive tradeoff. Screening a deep mutant library of the bla ampC beta-lactamase gene of Escherichia coli, we identified mutations that allow growth at beta-lactam concentrations far exceeding those inhibiting growth of the wildtype strain, even in the presence of the enzyme inhibitor (avibactam). These escape mutations are rare and drug-specific, and some combinations of avibactam with beta-lactam drugs appear to prevent such escape phenotypes. Our results, showing differential adaptive potential of bla ampC to combinations of avibactam and different beta-lactam antibiotics, suggest that it may be possible to identify treatments that are more resilient to evolution of resistance.

Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

“…For instance, Jahn et al demonstrated that variations in treatment dynamics can significantly alter evolved resistance for some antibiotics, such as tetracycline, but not others, such as amikacin and piperacillin ( 18 ). Other evolution experiments that were systematically conducted using a range of concentrations for β-lactams ( 19 ) and erythromycin ( 20 ) have highlighted the concentration-dependent adaptability of Escherichia coli .…”

Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes

“…These mutants are also likely to confer resistance to REL, NAC, and ZID. However, resistance to AVI can also arise from mutations to the Ω-loop and the H-10 helix (16,(44)(45)(46). Figure 3A).…”

Struggle To Survive: the Choir of Target Alteration, Hydrolyzing Enzyme, and Plasmid Expression as a Novel Aztreonam-Avibactam Resistance Mechanism

“…Aztreonam (ATM) is stable to the hydrolysis of MBLs ( 10 , 11 ), and the combination of aztreonam-avibactam (ATM-AVI) has activity against CPE producing serine-based carbapenemases, MBLs, or both and has the potential to be a major option for combatting CPE. Unfortunately, ATM-AVI-resistant strains have been found ( 12 – 14 ), but the resistance mechanisms remain poorly studied. In this study, we report a unique combination of ATM-AVI resistance mechanisms in Escherichia coli .…”