Microbial genomics as a strategy for developing antimicrobial drugs "failed to deliver" in part because "we don't understand the biology," says Eric Brown of McMaster University in Hamilton, Ontario, Canada.
His strategy to overcome that impasse involves using antibiotics to "probe biology" and thus learn more about "essential functions" of microbes en route, perhaps, to novel or improved antimicrobials. He spoke during the symposium, "A New World of Academic Antimicrobial Discovery," part of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Chicago, Ill., last September.
One approach is to follow what happens metabolically when Escherichia coli or other bacterial cells are treated with combinations of drugs, looking for "cryptic activity," as well as enhanced activity of antimicrobial agents that are mediocre when used alone, Brown says. Loperamide (Imodium), for example, appears to be weakly, if also "inherently antimicrobial," but proves synergistic with antibiotics such as tetracycline- at least in part because it helps them get into cells by altering bacterial cell membranes. In experiments to treat animals infected with salmonellae, combining such drugs in what he calls a "syncretic combination" yields a 6-log increase in efficacy. Such mixtures of antibiotics with nonantibiotics "have a fascinating potential," he says, noting that such "proof of principle" studies might apply to other drugs. Further, such combinations might prove "dose sparing to reduce [drug] toxicities."
Another symposium participant, Christopher Schofield of Oxford University in Oxford, United Kingdom, has a particular interest in _-lactam antibiotics and the inhibitors that target _-lactamase enzymes, which undercut the effectiveness of these antibiotics. The bacterial targets of these antibiotics remain worth hitting, but perhaps with novel agents lacking the vulnerable _-lactam structure, he reasons. For example, he and his collaborators are studying alkyl boronic acid compounds that target penicillinbinding proteins to interfere with bacterial cell wall synthesis. Some such compounds show promising activity against methicillin-resistant Staphylococcus aureus strains, he says.
When it comes to developing new antimicrobial molecular scaffolds, "it is hard to do anything new," says Richard Lee of St. Jude Children's Research Hospital in Memphis, Tenn., another symposium participant. That realization led him to reexamine spectinomycin, an inhibitor of protein synthesis that is a secondline drug for treating infections caused by Neisseria gonorrhoeae. One within a set of 80 spectinomycin- based compounds proved potent against Mycobacterium tuberculosis, leading to further structural tinkering that yielded compounds with better minimal inhibitory concentrations. The lead compound is "very safe, not cross-resistant to other anti-tuberculosis drugs, and not cross-resistant with other inhibitors of protein synthesis, and shows impressive activity against extensively drug-resistant strains of M. tuberculosis," he says.
"It's very encouraging."
Alexander Mankin at the University of Illinois in Chicago also is studying antibiotics that target bacterial protein synthesis, wondering why cells subject to very high levels of some of these inhibitors continue to produce small amounts of protein, a phenomenon called "protein escape." Perhaps the "better antibiotics allow more protein to be made," and might account for why some protein synthesis inhibitors are bactericidal, whereas others are bacteriostatic, he says. "It may be time to stop thinking that the ‘good' antibiotics are the ones that inhibit all polypeptide synthesis but [instead] are the drugs that allow some to be made."
Jeffrey L. Fox
Jeffrey L. Fox is the Microbe Current Topics and Features Editor.
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