Drugging evolution of antibiotic resistance at a regulatory network hub

• DOI: 10.1126/sciadv.adg0188
• Publication Date: 2023-06-23T18:10:27Z
• Authors: Yin Zhai; John P. Pribis; Sean W. Dooling; Libertad Garcia-V...; P.J. Minnick; Jun Xia; Jingjing Liu; Qian Mei; Devon M. Fitzgerald; Christophe Herman; P.J. Hastings; Mauro Costa-Mattioli; Susan M. Rosenberg
• Keywords: SOS response

Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life antibiotics, yet evolution-slowing drugs and drug targets have been underexplored ineffective. Here, we used network-based strategy identify that block hubs fluoroquinolone antibiotic-induced mutagenesis. We U.S. Food Drug Administration– European Medicines Agency–approved drug, dequalinium chloride (DEQ), inhibits activation Escherichia coli general stress response, which promotes ciprofloxacin-induced (stress-induced) mutagenic DNA break repair. uncover step in pathway inhibited: upstream “stringent” starvation find DEQ slows evolution without favoring proliferation DEQ-resistant mutants. Furthermore, demonstrate stress-induced during mouse infections its inhibition DEQ. Our work provides proof-of-concept for bacteria generally.