Many excellent reviews describing the genetics and biochemistry of the origins, evolution, and mechanisms of antibiotic resistance have appeared over the last 60 years. Fortunately, the number existing as functional resistance determinants in pathogens is much smaller. Medical pundits are now warning of a return to the preantibiotic era a recent database lists the existence of more than 20,000 potential resistance genes (r genes) of nearly 400 different types, predicted in the main from available bacterial genome sequences ( 85). Regrettably, the use of these wonder drugs has been accompanied by the rapid appearance of resistant strains. Antibiotics have revolutionized medicine in many respects, and countless lives have been saved their discovery was a turning point in human history. The discovery of these infectious agents in the late 19th century stimulated the search for appropriate preventative and therapeutic regimens however, successful treatment came only with the discovery and introduction of antibiotics half a century later. The most striking examples, and probably the most costly in terms of morbidity and mortality, concern bacteria. Many resolutions and recommendations have been propounded, and numerous reports have been written, but to no avail: the development of antibiotic resistance is relentless. Most international, national, and local agencies recognize this serious problem.

In the specific case of antimicrobial agents, the complexity of the processes that contribute to emergence and dissemination of resistance cannot be overemphasized, and the lack of basic knowledge on these topics is one of the primary reasons that there has been so little significant achievement in the effective prevention and control of resistance development. A wide range of biochemical and physiological mechanisms may be responsible for resistance. This is true for agents used in the treatment of bacterial, fungal, parasitic, and viral infections and for treatment of chronic diseases such as cancer and diabetes it applies to ailments caused or suffered by any living organisms, including humans, animals, fish, plants, insects, etc. The successful use of any therapeutic agent is compromised by the potential development of tolerance or resistance to that compound from the time it is first employed. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory. 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. 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. 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 is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. Summary: Antibiotics have always been considered one of the wonder discoveries of the 20th century.

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