In the race against microbes, researchers are scoring some points.

Three research groups have reported independent successes in the search for new antibiotics in recent weeks. Ranging from a cholera-specific molecule to a broad-spectrum agent that one reviewer compared to penicillin, the papers reported multiple novel mechanisms to attack both Gram-positive and Gram-negative bacteria, showing that though "novel" antibiotics often have been no more than tweaked versions of older drugs in recent years, there is no scientific reason why that needs to be the case.

In the November 2005 issue of Nature Medicine, available as an advance online publication, German researchers from Bayer HealthCare AG, located in Wuppertal, and the University of Bonn reported on second-generation acyldepsipeptides or ADEPs, compounds they developed by optimizing enzymes that were originally isolated from a marine bacterium.

ADEP-derived compounds act by binding to a regulator of the proteolytic machinery of Gram-positive bacteria. Thus deprived of self-control, bacterial proteolysis goes into overdrive. The bacterial proteolytic machinery, which usually restricts itself to the degradation of misfolded or otherwise defective proteins and the targeted breakdown of cell-cycle regulators, suddenly chows down indiscriminately on cytoplasmic proteins that are important to bacterial function. By a molecular mechanism that has not yet been determined, it ultimately inhibits bacterial cell division. In animal experiments, ADEP-derived compounds protected animals from infections Enterococcus faecalis infections, as well as Staphylococcus aureus-induced sepsis.

The authors said that in cells in the laboratory, ADEP resistance occurred at moderate frequency, which suggested the compound might be most useful clinically when used as part of a combination therapy. However, they also noted that "we did not observe a single ADEP-resistant strain among 200 recent staphylococcal isolates from U.S. hospitals, half of which were methicillin-resistant S. aureus strains," opening up the intriguing possibility that outside of the test tube, mutations that render S. aureus resistant to ADEP compounds also interfere with its ability to survive and/or cause illness.

Nature Medicine's sister publication Nature also has a recent paper on a new class of antibiotic, in its Oct. 13, 2005, issue. Like ADEP, the peptide plectasin is derived from a natural source - in that case, a fungus. The scientists, from the Danish and U.S. branches of the biotechnology company Novozymes A/S; the National Center for Antimicrobials and Infection Control in Copenhagen, Denmark; Danish company Novo Nordisk A/S; the David Geffen School of Medicine at UCLA; and Georgetown University Medical Center in Washington, isolated plectasin from a fungus. Structural studies showed that it is similar to defensins, a family of antimicrobial peptides. (See BioWorld Today, Sept. 30, 2005.)

While defensins have been found in both higher plants and animals from humans to invertebrates such as spiders and ticks, the Nature paper marked the first description of a defensin in a fungus. While most defensins work by binding to and weakening the membranes of infective invaders, plectasin might have a different mechanism of action, as it works much more slowly that other known members of its family. Plectasin was identified by routine screening methods; the scientists subsequently managed to produce large amounts of recombinant plectasin in another fungus, Asperilligus oryzae.

In the test tube, plectasin was active against several different types of bacteria, including a large number of clinical isolates of the pneumonia-causing bacterium S. pneumoniae. Most importantly, plectasin showed activity against every known drug-resistant S. pneumonia strain - 90 in all.

In mouse studies, plectasin showed low toxicity and cured them of experimental peritonitis with the same efficacy as vancomycin, and helped with pneumonia as well as penicillin does.

In a final paper on antibiotics, published in the Oct. 13, 2005, issue of Science online, researchers from Harvard Medical School reported on a compound named virstatin that is effective against the cholera bacterium Vibrio cholerae in mice.

In that case, the novel mechanism by which virstatin operates is to down-regulate bacterial virulence without outright killing the bacterium. In a bacterial screen, virstatin inhibited a transcriptional regulator of cholera, ToxT; that, in turn, prevented the expression of two critical V. cholerae virulence factors, cholera toxin and the toxin co-regulated pilus, which normally help the virus establish itself in its host during infection.

In animal experiments, virstatin protected infant mice from intestinal colonization by V. cholera bacteria, and, importantly for its clinical relevance, improved recovery when given after colonization already had been established. The authors concluded that "identification of inhibitors of virulence represents a new path to anti-infective discovery that is quite different from conventional approaches that target only bacterial processes that are essential both in vivo and in vitro."