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. 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. A wide range of biochemical and physiological mechanisms may be responsible for resistance. 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. Most international, national, and local agencies recognize this serious problem. Many resolutions and recommendations have been propounded, and numerous reports have been written, but to no avail: the development of antibiotic resistance is relentless.
The most striking examples, and probably the most costly in terms of morbidity and mortality, concern bacteria. 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. Antibiotics have revolutionized medicine in many respects, and countless lives have been saved; their discovery was a turning point in human history. Regrettably, the use of these wonder drugs has been accompanied by the rapid appearance of resistant strains. 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 . Fortunately, the number existing as functional resistance determinants in pathogens is much smaller.
Many excellent reviews describing the genetics and biochemistry of the origins, evolution, and mechanisms of antibiotic resistance have appeared over the last 60 years. Two of note in recent times are those of Levy and Marshall and White et al. . The goal of this short article is not to summarize such a wealth of information but to review the situation as we see it now (most particularly with respect to the origins and evolution of resistance genes) and to provide some personal views on the future of antibiotic therapy of infectious diseases.
Antibiotic discovery, modes of action, and mechanisms of resistance have been productive research topics in academia and, until recently, in the pharmaceutical industry. As natural products, they provide challenging intellectual exercises and surprises with respect to their chemical nature, biosynthetic pathways, evolution, and biochemical mode of action , . The total synthesis of such natural products in the laboratory is difficult, since these small molecules are often extremely complex in functionality and chirality . The antibiotic penicillin was discovered in 1928, but the complete structure of this relatively simple molecule was not revealed until 1949, by the X-ray crystallographic studies of Dorothy Crowfoot Hodgkin , and was confirmed by total synthesis in 1959 . Studies of modes of action have provided biochemical information on ligands and targets throughout antibiotic history ,, and the use of antibiotics as “phenotypic mutants” has been a valuable approach in cell physiology studies . The field of chemical biology/genetics grew from studies of those interactions. We have a meager understanding of how antibiotics work, and in only a few instances can the intimate interactions of the small molecule and its macromolecular receptor be interpreted in terms of defined phenotypes. More surprisingly, there is a paucity of knowledge of the natural biological functions of antibiotics, and the evolutionary and ecological aspects of their chemical and biological reactions remain topics of considerable interest and value .
To begin, the definition of “antibiotic,” as first proposed by Selman Waksman, the discoverer of streptomycin and a pioneer in screening of soils for the presence of biologicals, has been seriously overinterpreted; it is simply a description of a use, a laboratory effect, or an activity of a chemical compound . It does not define a class of compound or its natural function, only its application. At the risk of attack from purist colleagues, the generic term “antibiotic” is used here to denote any class of organic molecule that inhibits or kills microbes by specific interactions with bacterial targets, without any consideration of the source of the particular compound or class. Thus, purely synthetic therapeutics are considered antibiotics; after all, they interact with receptors and provoke specific cell responses and biochemical mechanisms of cross-resistance in pathogens. The fluoroquinolones (FQs), sulfonamides, and trimethoprim are good examples.
As in any field of biological study, antibiotic history is replete with misconceptions, misinterpretations, erroneous predictions, and other mistakes that have occasionally led to the truth. This account aspires to focus on the truth. The discovery of antibiotics is rightly considered one of the most significant health-related events of modern times, and not only for its impact on the treatment of infectious diseases. Studies with these compounds have often shown unexpected nonantibiotic effects that indicate a variety of other biological activities; the result has been a significant number of additional therapeutic applications of “antibiotics” as antiviral, antitumor, or anticancer agents. In some cases, the alternative applications have surpassed those of antibiotic activity in importance, such as in the treatment of cardiovascular disease or use as immunosuppressive agents .
Unfortunately, the colossal need for these valuable drugs has had a significant environmental downside. In the 60 years since their introduction, millions of metric tons of antibiotics have been produced and employed for a wide variety of purposes. Improvements in production have provided increasingly less expensive compounds that encourage nonprescription and off-label uses. The cost of the oldest and most frequently used antibiotics is (probably) mainly in the packaging. The planet is saturated with these toxic agents, which has of course contributed significantly to the selection of resistant strains. The development of generations of antibiotic-resistant microbes and their distribution in microbial populations throughout the biosphere are the results of many years of unremitting selection pressure from human applications of antibiotics, via underuse, overuse, and misuse. This is not a natural process, but a man-made situation superimposed on nature; there is perhaps no better example of the Darwinian notions of selection and survival.
