Beneficial impact of acquired AmpC β-lactamases on bacterial fitness and pathogenicity: a new paradigm

Although β-lactamases have always been considered enzymes involved in resistance to β-lactam antibiotics, they also have to be considered as playing a role in reshaping bacterial physiology. By studying a series of class C β-lactamases, we uncovered an unexpected dual role. Besides conferring resistance to β-lactams, they also impact bacterial growth, motility, and pathogenicity through modulation of flagellar biosynthesis. Strikingly, while CMY-42- and CMY-145-producing recombinant Escherichia coli strains showed enhanced in vitro fitness growth by reducing energy-costly flagellar production, production of CMY-2 (the most commonly identified acquired AmpC β-lactamase identified in Enterobacterales) restored flagella and increased virulence in vivo. This work reframes β-lactamases as metabolic regulators influencing ecological success, offering new insight into how resistance determinants promote the spread and clinical impact of Enterobacterales.