as growth promotants. This is a new phenomenon in the history of antimicrobials and one with significant implications for what Silbergeld referred to as the “resistome.”
The term “resistome” was introduced by Wright (2007), who defined it as the collection of all the antibiotic resistance genes and their precursors in the entire microbial community of both pathogenic and nonpathogenic bacteria. Genes within the resistome encode molecular changes that confer phenotypic resistance to both general and specific antibiotic molecules. They are often clustered in cassettes and are transferable by plasmids, creating a pleiotropic efficacy. Multigene cassettes can encode other phenotypes, not just resistance.
An important feature of the resistome is that resistance genes are readily transferred from one bacterial cell to another via horizontal, or lateral, gene transfer (usually via plasmid-mediated transfers but also by conjugation). The classic model of antibiotic resistance describes a population of diverse organisms encountering antibiotic pressure, with some organisms being susceptible and some resistant and with the susceptible organisms dying and the resistant organisms persisting (Sommer and Dantas, 2011). However, that model does not account for the dynamic nature of horizontal gene transfer and the fact that a population of initially susceptible bacteria can accumulate expressible resistance genes over time. Even after a stressor is withdrawn, this system can be permanently altered by the experience. In a study of humans exposed to ciprofloxacin, Dethlefsen and Relman (2011) showed that resistant phenotypes persisted even after exposure ended.
Increasingly, horizontal gene transfer involves not just the sharing of single genes, but also the sharing of cassettes of multiple genes. Silbergeld explained how the extensive use of antimicrobials exerts multiple and repeated pressures on bacterial populations, resulting in sequential acquisition of resistance genes and buildup of multigene cassettes (Canton and Ruiz-Garbajosa, 2011). As empirical evidence of the buildup of transferable multigene cassettes, Silbergeld mentioned U.S. Department of Agriculture (USDA) data showing growth over time of extended multidrug resistance phenotypes of Escherichia coli in domestic animals (i.e., chicken, swine, cat, dog, dairy cattle) (Lindsey et al., 2011).
Not only is the resistome accruing more resistance genes, either singly or bundled in multigene cassettes, it also appears to be accumulating networks of preferential horizontal gene transfers, or “cliques” (Skippington and Ragan, 2011). Again, extensive antimicrobial use is exerting selective pressure, in this case for more active networks of horizontal gene transfer.