Biology subjects

Sorum, V.

Publications and source records attributed to Sorum, V..

4 recordsLinked to original sources

bioRxiv2022

Evolution of β-lactamase mediated cefiderocol resistance

Cefiderocol is a novel siderophore {beta}-lactam with improved hydrolytic stability toward {beta}-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 {beta}-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 {beta}-lactamase-mediated resistance development. First, we investigated how the expression of different {beta}-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 {beta}-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 {beta}-lactam drugs. Taken together, contemporary {beta}-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. SummaryDespite the reported higher stability of cefiderocol against {beta}-lactamase hydrolysis, we show that the expression of {beta}-lactamases from different Ambler classes significantly contributes to cefiderocol resistance and that these enzymes have the evolutionary potential to evolve towards increasing cefiderocol concentrations.

molecular biology↗

bioRxiv2021

Evolutionary instability of collateral susceptibility networks in ciprofloxacin resistant clinical Escherichia coli strains

Collateral sensitivity and resistance occur when resistance development towards one antimicrobial either potentiates or deteriorates the effect of others, respectively. Previous reports on collateral effects on susceptibility focus on newly acquired resistance determinants and propose that novel treatment guidelines informed by collateral networks may reduce the evolution, selection and spread of antimicrobial resistance. In this study, we investigate the evolutionary stability of collateral networks in five ciprofloxacin resistant, clinical Escherichia coli strains. After 300 generations of experimental evolution without antimicrobials, we show complete fitness restoration in four of five genetic backgrounds and demonstrate evolutionary instability in collateral networks of newly acquired resistance determinants. We show that compensatory mutations reducing efflux expression is the main driver destabilizing initial collateral networks and identify rpoS as a putative target for compensatory evolution. Our results add another layer of complexity to future predictions and clinical application of collateral networks.

microbiology↗

bioRxiv2019

Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria

Mobile genetic elements (MGEs), such as plasmids, promote bacterial evolution through horizontal gene transfer (HGT). However, the rules governing the repertoire of traits encoded on MGEs remain unclear. In this study, we uncovered the central role of genetic dominance shaping genetic cargo in MGEs, using antibiotic resistance as a model system. MGEs are typically present in more than one copy per host bacterium and, as a consequence, genetic dominance favors the fixation of dominant mutations over recessive ones. Moreover, genetic dominance also determines the phenotypic effects of horizontally acquired MGE-encoded genes, silencing recessive alleles if the recipient bacterium already carries a wild-type copy of the gene. The combination of these two effects governs the catalogue of genes encoded on MGEs, dictating bacterial evolution through HGT.

microbiology↗

bioRxiv2018

Conserved collateral susceptibility networks in diverse clinical strains of Escherichia coli.

There is urgent need to develop novel treatment strategies to reduce antimicrobial resistance. Collateral sensitivity (CS), where resistance to one antimicrobial increases susceptibility to other drugs, is a uniquely promising strategy that enables selection against resistance during treatment. However, using CS-informed therapy depends on conserved CS networks across genetically diverse bacterial strains. We examined CS conservation in 10 clinical strains of E. coli resistant to four clinically relevant antibiotics. Collateral susceptibilities of these 40 resistant mutants were then determined against a panel of 16 antibiotics. Multivariate statistical analyses demonstrate that resistance mechanisms, in particular efflux-related mutations, as well as relative fitness were principal contributors to collateral changes. Moreover, collateral responses shifted the mutant selection window suggesting that CS-informed therapies could affect evolutionary trajectories of antimicrobial resistance. Our data allow optimism for CS-informed therapy and further suggest that early detection of resistance mechanisms is important to accurately predict collateral antimicrobial responses.

microbiology↗