On the origin of plasmid-borne, extended-spectrum, antibiotic resistance mutations in bacteria

Many antibiotic resistance mutations arise in pathogenic bacteria that harbor plasmids (R-plasmids). Resistance to third generation cephalosporins, for instance, largely occurs by one or more point mutations in plasmid bla genes that expand the resistance spectrum of beta-lactamases. Here I review relevant evidence underlying the worldwide emergence of extended spectrum beta-lactamases (ESBLs). The conclusion reached is that the origin of these resistance-conferring mutations cannot be explained by a series of single point mutation and selection events. Instead, highly advantageous stochastic processes might exist that generate alterations in the sequence or the conformation of particular regions in chromosomal or plasmid genomes such as bla, i.e., recombination or mutation. Several explanations for the origin of ESBLs are reviewed but direct experimental evidence to support or to invalidate them is still lacking. The cellular conditions under which ESBLs arise are unknown; however, involvement of nutritional stresses inside natural animal hosts and of plasmid conjugal functions appear likely.