Expression
of β-lactamase is the single most prevalent determinant
of antibiotic resistance, rendering bacteria resistant to β-lactam
antibiotics. In this article, we describe the development of an antibiotic
prodrug that combines ciprofloxacin with a β-lactamase-cleavable
motif. The prodrug is only bactericidal after activation by β-lactamase.
Bactericidal activity comparable to ciprofloxacin is demonstrated
against clinically relevant E. coli isolates expressing
diverse β-lactamases; bactericidal activity was not observed
in strains without β-lactamase. These findings demonstrate that
it is possible to exploit antibiotic resistance to selectively target
β-lactamase-producing bacteria using our prodrug approach, without
adversely affecting bacteria that do not produce β-lactamase.
This paves the way for selective targeting of drug-resistant pathogens
without disrupting or selecting for resistance within the microbiota,
reducing the rate of secondary infections and subsequent antibiotic
use.
Emerging resistance to current antibiotics raises the need for new microbial drug targets. We show that targeting branchedchain amino acid (BCAA) biosynthesis using sulfonylurea herbicides, which inhibit the BCAA biosynthetic enzyme acetohydroxyacid synthase (AHAS), can exert bacteriostatic effects on several pathogenic bacteria, including Burkholderia pseudomallei, Pseudomonas aeruginosa, and Acinetobacter baumannii. Our results suggest that targeting biosynthetic enzymes like AHAS, which are lacking in humans, could represent a promising antimicrobial drug strategy.
Nasal colonization by the pathogen Staphylococcus aureus is a risk factor for subsequent infection. Loss of function mutations in the gene encoding the virulence regulator Rsp are associated with the transition of S. aureus from a colonizing isolate to one that causes bacteraemia. Here, we report the identification of several novel activity-altering mutations in rsp detected in clinical isolates, including for the first time, mutations that enhance agr operon activity. We assessed how these mutations affected infection-relevant phenotypes and found loss and enhancement of function mutations to have contrasting effects on S. aureus survival in blood and antibiotic susceptibility. These findings add to the growing body of evidence that suggests S. aureus ‘trades off’ virulence for the acquisition of traits that benefit survival in the host, and indicates that infection severity and treatment options can be significantly affected by mutations in the virulence regulator rsp.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.