Genetic Mechanisms of Transfer of Drug Resistance

Resistance to antibiotics in clinical bacteria has closely followed the introduction of each antibiotic. Resistance to sulfa drugs and penicillin was known in the 1940s, and the transmissibility of resistance to sulfa drugs, streptomycin, chloramphenicol, and tetracycline became known during the following decade. In the course of studies on bacillary dysentery in Japan, it was found that drug resistances could be transferred together from Shigella to Escherichia coli. Many of these studies were published in Japanese. A key review by Watanabe (1) summarized these studies and, in retrospect, was exceptionally insightful. It introduced the concept of R factors, made up of RTF (resistance transfer factor) and individual resistance genes. R factors were recognized as plasmids, and even the phenomenon of fertility inhibition of F factor by some R factors (now known to be IncF plasmids) was observed. The RTF is now known to be composed of the replication and transfer functions of the plasmids, and the genes in these studies are now known to be on mobile elements (simple and composite transposons and integrons). The 1960s and 1970s saw a rapid increase in the number of antibiotics (particularly aminoglycosides and -lactams) and a concomitant increase in the number and types of resistance genes. Mapping of plasmids by restriction enzyme digests and electron microscopy of heteroduplexes gave an idea of how DNA rearrangements were taking place, but only after the advent of DNA sequencing in the late 1970s could the variety and complexity of genetic mechanisms of resistance gene dissemination be appreciated.