Evolution of β-lactamase mediated cefiderocol resistance

Abstract

Cefiderocol is a novel siderophore β-lactam with improved hydrolytic stability toward β-lactamases, including carbapenemases, achieved by combining structural moieties of two clinically efficient cephalosporins, ceftazidime and cefepime. Consequently, cefiderocol represents a treatment alternative for infections caused by multi-drug resistant Gram-negatives. Using directed evolution on a wide variety of different β-lactamases, such as KPC-2 and CTX-M-15 (Ambler class A), NDM-1 (class B), CMY-2 (class C) and OXA-48 (class D), we studied the role of cefiderocol during β-lactamase-mediated resistance development. First, we investigated how the expression of different β-lactamases causes changes in cefiderocol susceptibility. In a low-copy number vector, we found that OXA-48 and KPC-2 conferred non or marginal decreases in cefiderocol susceptibility, respectively. On the contrary, CMY-2, CTX-M-15 and NDM-1 substantially decreased cefiderocol susceptibility by 16-, 8- and 32-fold, respectively. Second, we determined the evolutionary potential of these enzymes to adapt to increasing concentrations of cefiderocol. Our data show that with the acquisition of only 1 to 2 mutations, all β-lactamases were evolvable to further cefiderocol resistance by 2- (NDM-1, CTX-M-15), 4- (CMY-2), 8- (OXA-48) and 16-fold (KPC-2). Cefiderocol resistance development was often associated with collateral susceptibility changes including increased resistance to ceftazidime and ceftazidime-avibactam as well as functional trade-offs against different β-lactam drugs. Taken together, contemporary β-lactamases of all Ambler classes can potentially contribute to cefiderocol resistance development and can acquire mutations allowing them to adapt to increasing cefiderocol concentration. At the same time, resistance development caused clinically important cross-resistance, especially against ceftazidime combinations.

A glucose-mediated antibiotic resistance metabolic flux from glycolysis, the pyruvate cycle, and glutamate metabolism to purine metabolism

“…This drug has a broad spectrum of activity against Gram-positive and Gram-negative aerobic bacteria, particularly Pseudomonas aeruginosa and Enterobacteriaceae (including beta-lactamase-positive strains) (Richards and Brogden, 1985). However, the long-term use and wide use of ceftazidime cause the development of drug resistance in clinical isolates (Sanz-García et al, 2018;Fröhlich et al, 2022). Not only in humans but also in untreated wastewater environments and aquaculture, ceftazidime-resistant bacteria are widespread (Adelowo et al, 2018;Salgueiro et al, 2021;Moya-Salazar et al, 2022), which poses a challenge to control infection caused by the resistant pathogens in hospitals and aquaculture.…”