Scattered Progress by Reexamining the Familiar in Quest for Antimicrobials
Like its predecessors, the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Toronto, Ontario, Canada, last September, was awash in reports on promising new antimicrobial agents. Many belong to familiar classes of drugs, but present some advantage or another over their siblings-or rather their aunts and uncles. All are beset by the challenges of going beyond proving in vitro effects to establish genuine efficacy and safety features. Here are some selected highlights, with apologies for the many candidate drugs that could not be represented.
The first members in the class of macrolide antibiotics were discovered nearly a half-century ago, and there have been three main "waves" of them since then, according to Andre Bryskier of Aventis Pharmaceuticals in Romainville, France, who spoke during the symposium, "What New Advances Can We Expect from Existing Antiinfective Classes?" However, waves of pathogens manifesting resistance tend to follow each wave of new macrolides. For instance, in Europe, the United States, and elsewhere there is widespread resistance to the familiar macrolide erythromycin among isolates of the pathogen Streptococcus pneumoniae, a major cause of community-acquired pneumonia, he says.
However, such isolates remain sensitive to the ketolides, a class of semisynthetic derivatives of erythromycin, some of whose members show promise for being part of the next macrolide wave, according to Bryskier. Referring to telithromycin as the prototype of this subclass, he points out that it is bactericidal, capable of "5 logs of killing." It works by inhibiting protein synthesis-albeit by a somewhat different means than does erythromycin. Thus, this ketolide seems not only to bind to 50S ribosomal units in bacterial cells but also to 30S subunits, perhaps accounting for why it remains active against them and inhibits protein synthesis even in bacterial isolates that are resistant to erythromycin, he points out. Moreover, it can overcome a common drug-efflux mechanism whereby some pathogens gain resistance to several antibiotics at once.
In a similar spirit, the venerable class of beta-lactam antibiotics can still be counted on to yield new agents that are safer and more potent than many of their predecessors, according to Michael Dudley of Microcide Pharmaceuticals, Inc., in Mountain View, Calif. Some of the newer beta-lactam compounds are "built to have high activity" against pathogens and, thus, are "not your father's Oldsmobile," he says. Several carbapenem compounds, including some with enhanced oral availability, and additional cephalosporins are now being evaluated, and they may be expected to provide help in combating infections in hospital settings and also in sparing the use of fluoroquinolones when used to combat community-acquired respiratory infections.
The first quinolone antibiotics were discovered in the 1960s, and two decades later this class came to be dominated by the fluoroquinolones, according to Carl Catrenich of Procter & Gamble Pharmaceuticals in Mason, Ohio, who spoke during the symposium, "Quinolone Structure-activity Relationships (SAR): Back and Forth." However, he says, "If proper constituents are chosen, nonfluorinated quinolone (NFQs) compounds can be designed with more potency than the fluorinated derivatives." He and his collaborators are testing a sizable number of NFQs, and find that many of them perform "better than the benchmark" antibiotics in a series of tests, particularly when being evaluated against drug-resistant strains. Some of the NFQs, which show promising "broad-spectrum" activity and appear in vitro to be "less susceptible to the development of resistance and cross-resistance," may well offer an "opportunity to improve on the fluoroquinolones," he says.
Some of the energy devoted to finding and developing new antimicrobial agents is directed to finding drugs active against fungal pathogens. Amphotericin B in its own class and the azoles are the dominant antifungal agents now in widespread clinical use. But considerable interest and hope now focuses on several members of another class of antifungal drugs, the echinocandins, according to John Rex of the University of Texas Medical School in Houston. Although initially studied in the 1980s and soon abandoned because of solubility problems, three newer representatives of this class are now "pretty far along in clinical development," he says.
The echinocandins appear to work by inhibiting the enzyme glucan synthase but certainly interfere in some way with the synthesis of glucan, which is a component of the fungal wall, Rex says. Because wall synthesis is "distinctly a property of fungi, inhibiting it can be lethal, and there should be no cross-resistance with other antifungal drugs." All three of the echinocandins now being evaluated clinically appear to have long half-lives, outstanding safety profiles, good solubility but poor oral availability, and decent antifungal activities, albeit tending to be "more static than cidal" against Aspergillus, a particularly difficult fungal pathogen, he notes. In general, the activity against various Candida species is "stellar," he adds, while the somewhat poorer efficacy against Aspergillus species may be overcome by using the echinocandins in combination with other antifungal agents.
Jeffrey L. Fox