Despoina Mavridou Ph.D.

Seminar Details

Host: Paul Straight, Ph.D.

Time: 4:00 pm

Location: BICH 108

Seminar Abstract

Antibiotic resistance proteins expand or diversify their activity spectra through the rapid accumulation of mutations, leading to the emergence of bacterial strains that are no longer amenable to antibiotic treatment. Although powerful variants of resistance proteins have been subject to intense characterization, identification of broad drivers for resistance evolution remains elusive, and generation of strategies to mitigate it are non-existent. We have discovered that oxidative protein folding controls the expansion of the hydrolytic activity of β-lactamases, proteins that break down invaluable drugs like penicillin. We find that removal of conserved disulfide bonds from enzymes with narrow-hydrolytic spectra blocks their evolution to their broad-spectrum counterparts, while addition of disulfides in β-lactamases normally devoid of these linkages drastically expands their mutational landscapes. Moreover, we show that disulfide bonds act as anchors that facilitate the folding of evolved broad-spectrum enzymes, their presence offsetting the burden that functional mutations impose on protein biogenesis. Finally, since disulfide formation is catalysed by the central cell envelope oxidative pathway in bacteria, we demonstrate that targeting this process can limit genetic innovation in β-lactamases in vitro and in vivo, thus opening new avenues towards strategies that impede the evolution of antimicrobial resistance.