Cooperative antibiotic resistance facilitates horizontal gene transfer

The rise of beta-lactam resistance among pathogenic bacteria, due to the horizontal transfer of plasmid-encoded beta-lactamases, is a current global health crisis. Importantly, beta-lactam hydrolyzation by beta-lactamases, not only protects the producing cells but also sensitive neighboring cells cooperatively. Yet, how such cooperative traits affect plasmid transmission and maintenance is currently poorly understood. Here we experimentally show that KPC-2 beta-lactamase expression and extracellular activity were higher when encoded on plasmids compared with the chromosome, resulting in the elevated rescue of sensitive non-producers. This facilitated efficient plasmid transfer to the rescued non-producers and expanded the potential plasmid recipient pool and the probability of plasmid transfer to new genotypes. Social conversion of non-producers by conjugation was efficient yet not absolute. Non-cooperative plasmids, not encoding KPC-2, were moderately more competitive than cooperative plasmids when beta-lactam antibiotics were absent. However, in the presence of a beta-lactam antibiotic, strains with non-cooperative plasmids were efficiently outcompeted. Moreover, plasmid-free non-producers were more competitive than non-producers imposed with the metabolic burden of a plasmid. Our results suggest that cooperative antibiotic resistance especially promotes the fitness of replicons that transfer horizontally such as conjugative plasmids.

Automated summary

The rise of beta-lactam resistance due to the transfer of plasmid-encoded beta-lactamases is a global health crisis. Expressing beta-lactamase on plasmids enhances its activity and promotes the transfer of plasmids to non-producers, expanding the potential recipient pool. Cooperative plasmids are more competitive in the presence of a beta-lactam antibiotic, while plasmid-free non-producers are more competitive than those burdened with a plasmid. This suggests that cooperative antibiotic resistance benefits the fitness of horizontally transmitting replicons like conjugative plasmids.