The Past

In the so-called golden age of antibiotic discovery, all existing antibiotic classes were found by fairly simple MIC (minimal inhibitory concentration) type tests, in which the suppression of the growth of a low inoculum of bacteria in a test tube to visible optical densities was measured in rich growth media. Only much later did it become possible to understand at the molecular level how these compounds acted. As a rule, it took years, up to decades of work for several competing groups of scientists to elucidate the molecular details of their mode of action. In the very early days, many compounds (e.g., penicillin G, erythromycin, streptomycin, and tetracycline, to mention just a few) were detected in such simple growth tests with extracts from bacteria and fungi. After isolation of the active principle and structure determination they were brought right into the clinic without further modification. Thus, the early antibiotic classes stemmed almost exclusively from natural products produced by bacteria or fungi, and it is believed that microorganisms produce those so-called secondary metabolites to combat other microorganisms which compete for their ecological niches. In fact, the term "antibiotic" reflects that origin, although it is nowadays used for all antibacterial compounds, synthetic as well as natural-product-derived.

It is interesting to note that, indeed, a huge number of such antibiotics have been discovered by such simple MIC screening procedures; an excellent overview about the large number of structurally diverse natural compounds with antibacterial properties can be found in Ref. [7]. However, most representatives of this pool of antibacterial agents showed some unwanted properties, for example, with respect to antibacterial spectrum or toxicity. Since, seemingly, enough novel compounds without such unwanted properties could be found, only the latter were selected for further development, and, eventually, taken into the hospitals.

While it is hardly possible to overestimate the role of natural compound chemistry in those pioneer years, it soon became obvious that man-made, synthetic chemistry had a very important role to play, too. Firstly, the examples of the sulfonamides and the quinolones showed that it was possible to discover and introduce into clinical practice fully synthetic compounds with selective broad-spectrum antibacterial activity. The high chemical variability of such synthetic compounds was exploited with extremely gratifying success to optimize their properties with respect to, e.g., microbial spectrum, side-effect profile, kinetics, including oral availability, and drug interactions. Secondly, it turned out that similarly beneficial properties could be reached when semisynthetic or even fully synthetic variants of the natural products were produced. An additional rational for chemical variation within the same compound class was the observation that bacterial resistance development can be overcome at least partially by compound modification. A striking example is provided by penicillin and its derivatives. When penicillin G was discovered, almost all staphylococcal strains were susceptible to the drug, but the first b-lactamase-producing strains were already detected soon after its introduction into clinical practice [8], and shortly afterwards more than 80% of all staphylococcal isolates proved to be resistant by this mechanism. However, chemical modification of the b-lactam side chain resulted in novel penicillin derivatives (e.g., methicillin) which were no longer amenable to the hydrolyzing activity of the staphylococcal b-lactamases. Needless to say, this race between bacteria and scientists continues to this day. Thus, shortly after the introduction of methicillin in 1960, the first methicillin-resistant S. aureus strains were detected [9], which evaded the drug action by a completely different mechanism, namely the acquisition of an extra target protein, PBP 2a, with a much lower affinity for b-lactam antibiotics than the standard set of staphylococcal target proteins, PBPs 1-4 (for review, see, e.g., Ref. [10]).

The seamless stream of novel compound classes and the ability to overcome resistance problems at least to some extent within a certain class led to a clear decline in the antimicrobial discovery activities of industrial, academic, and public health groups, because the "problem" appeared to be largely solved. Not before the late 1980s and 1990s did it became clear how misconceived this expectation was. In fact, an unprecedented resistance development took place, at the beginning mostly confined to hospitals, but which has since also alarmingly spread into the community. Fortunately, this led to a revitalization in antibiotic drug discovery, and, for those companies and academic groups who never stopped, to an increase in efforts to effectively combat bacterial pathogens. The unprecedented progress made in the molecular understanding of microbial pathogens and the mechanisms of drug action in just that time period played an important role in this process, which brings us right to the present era in antibiotic discovery efforts.

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