Origins and evolution of antibiotic resistance

Abstract

Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.

FIG. 1.

History of antibiotic discovery and concomitant development of antibiotic resistance. The dark ages, the preantibiotic era; primordial, the advent of chemotherapy, via the sulfonamides; golden, the halcyon years when most of the antibiotics used today were discovered; the lean years, the low point of new antibiotic discovery and development; pharmacologic, attempts were made to understand and improve the use of antibiotics by dosing, administration, etc.; biochemical, knowledge of the biochemical actions of antibiotics and resistance mechanisms led to chemical modification studies to avoid resistance; target, mode-of-action and genetic studies led to efforts to design new compounds; genomic/HTS, genome sequencing methodology was used to predict essential targets for incorporation into high-throughput screening assays; disenchantment, with the failure of the enormous investment in genome-based methods, many companies discontinued their discovery programs. Other milestones in this history include the creation of the FDA Office of New Drugs after the thalidomide disaster led to stricter requirements for drug safety, including the use of antibiotics. This slowed the registration of novel compounds. Before antibiotics were discovered, Semmelweis advocated hand washing as a way of avoiding infection; this practice is now strongly recommended as a method to prevent transmission.

FIG. 2.

Numbers of unique β-lactamase enzymes identified since the introduction of the first β-lactam antibiotics. (Up-to-date numbers are courtesy of Karen Bush.)

FIG. 3.

Worldwide distribution of different classes of CTX-M β-lactamases (first identified in 1989). (Reprinted from reference by permission of Oxford University Press.)

FIG. 4.

Dissemination of antibiotics and antibiotic resistance within agriculture, community, hospital, wastewater treatment, and associated environments. (Adapted from reference and reference with permission of the publishers.)

FIG. 5.

Integron structure and gene capture mechanism. This figure indicates the basic elements of integrons, as found in bacterial genomes. The structure consists of an integrase (Int) with the P_int and P_C promoters in the 3′ end of the gene, with its associated cassette attachment or insertion site (attI). The integrase catalyzes the sequential recombination of circularized gene cassettes into the distal attachment site to create an operon-like arrangement (ant1^r, ant2^r, and so on) of r genes transcribed from the strong P_C promoter (132). Three classes of integrons have been identified that differ in their integrase genes.