Higher-order epistasis drives evolutionary unpredictability toward novel antibiotic resistance.

ABSTRACT: The rapid evolution of extended-spectrum β-lactamases (ESBLs) represents a global health threat, undermining the efficacy of β-lactams, the most extensively used antibiotic class. To elucidate the evolutionary dynamics underlying β-lactam resistance, we constructed a comprehensive combinatorial mutant library comprising all 55,296 possible TEM-1 β-lactamase variants integrating 18 clinically observed mutations across 13 key residues. Over eight million empirical fitness measurements were obtained under selection pressure with both a native antibiotic substrate (ampicillin) and a novel antibiotic (aztreonam), establishing the largest experimentally determined fitness landscape for antibiotic resistance to date. Through graph-theoretic and epistatic analyses, we discovered that selection wit

SUBMITTER: Gaszek IK 

PROVIDER: S-EPMC12265529 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature