Functionally redundant forms of extended-spectrum beta-lactamases and aminoglycoside modifying enzymes drive the evolution of two distinct multidrug resistance gene clusters in clinical populations of EXPEC

We evaluate the distribution of genetic markers for antibiotic resistance in 276 genomic sequences of Extraintestinal Pathogenic E. coli from two hospitals on the U.S. West coast. Plasmid-borne genes encoding drug-inactivating enzymes dominate the distribution of aminoglycoside and {beta}-lactam resistance markers. These genes can be assigned based on their distribution to two mutually exclusive complementarity groups (CGs: CG1 and CG2) with each displaying genetic linkage and minimal functional overlap. CG1 includes genes encoding OXA-1 and AAC(6)-Ib-cr, frequently also CTX-M-15, and sometimes AAC(3)-IIe.2, a variant of AAC(3)-IIe; CG2 includes AAC(3)-IId tightly linked to TEM-1, and occasionally also to genes encoding CTX-M-14-like {beta}-lactamases. This binary distribution of aminoglycoside and {beta}-lactamase resistance genes suggests a convergence between two different evolutionary solutions, and results in a ubiquitous functional redundancy in the clinical populations. CG1 and CG2 are largely carried in IncF plasmids, of which we distinguish seven classes based on Rpt-A1 sequence homology. Both CG1 and CG2 genes are found in two different IncF plasmid classes, demonstrating their pervasive mobility across plasmid backbones. Different CG genes and IncF plasmid classes are found in a wide range of MLSTs, highlighting the prevalence of horizontal gene transfer. We also identify at least five clonally expanding MLSTs, which represent high-risk clones: ST131, ST95, ST73, ST127, and ST69. The identification of clonally-expanding types, the discovery of CGs that are ubiquitously spread in diverse clinical strains, and the functional redundancy that these two groups represent have significant implications for monitoring and controlling the spread of resistance.