Antibiotic resistance and the golden age of microbiology

The ability of micro-organisms to develop resistance to the action of inhibitors has been known since the discovery of antimicrobial agents. The first reports were concerned with agents such as Salvarsan and Prontosil in the early 1900s; the phenomenon of ‘fastness’ to these agents was observed frequently during treatment with the drugs. Following the development of the sulfonamides in the 1940s and discovery of the ‘true’ antibiotics, those produced by fermentation such as penicillin, streptomycin, tetracycline, etc. in the 1950s, the study of antibiotic resistance and its mechanisms paralleled those concerned with mode of action. In the first place, the genetic characterization of a specific resistance mechanism was a critical step in defining antibiotic mode of action. The identification of a binding site or the accumulation of a biosynthetic intermediate provided important clues to the ways by which the antibiotics acted on microbes. To cite a specific case, mutants resistant to the aminoglycosides were early identified as alterations in ribosome structure, and these provided critical information about the structure of ribosomes and their functions in the translation process. The identification of these key components led to the characterization of antibiotic target sites within the ribosome structure: these have been confirmed by X-ray crystallographic studies (1). Similar analyses have revealed detailed molecular information on the targets for most classes of antibiotics. Interestingly, one phenotype that has never been adequately described is that of mutants that are dependent on the presence of antibiotics (such as streptomycin) for ribosome function in translation. Antibiotic resistance (AR) has become a field of research in its own right, and deciphering the widespread biochemical mechanisms involved have revealed significant information about the biology of microbes (2). Resistance has compromised the use of every therapeutic agent ever discovered. At the end of the Second World War, extensive use of antibiotics was accompanied by drastic increases in susceptibility of hospital pathogens and led to clinical failures in many hospitals (3). As antibiotic use increased on a worldwide scale, it was discovered that antibiotic resistance developed not only by mutation but by an alternative mechanism, that of horizontal gene transfer. Initial reports of transferable multidrug resistance by R factors in Japan in 1959 were greeted by scepticism in other countries, but soon the phenomenon was confirmed worldwide. It is now accepted as the principal, clinically significant route to antibiotic resistance in microbes. There are notable exceptions; for example, no transferable antibiotic resistance has been reported in the mycobacteria. There is a missing link in the evolution of R factors: they were first identified in Japan and subsequently in Europe and the US. Were R factors formed in the first years of extensive antibiotic use? Examination of bacterial pathogens isolated and stored from the 1930s showed no evidence for transferable antibiotic resistance at this time (4); however, the strains did contain plasmids. How and where did R factors evolve? Their discovery was the genesis of much exciting research, and, some 30 years later, horizontal gene transfer provided the foundation for practical genetic engineering and the creation of the biotechnology industry. Gene transfer between bacteria is considered to be ancient and universal and is an important element in theories of cellular evolution and in the formation and maintenance of microbial communities. Mutation is one thing, but where do resistance genes come from?