Adapt and survive: Novel antibiotics

Chemical modification of compromised antibiotics is giving them a new lease of life.

Aminoglycosides have been used for many years to treat a range of bacterial infections. As with all antibiotics, though, the emergence of drug-resistant strains is a significant and growing problem. Using an understanding of the drugs' structure and the mechanisms of resistance, Achaogen Inc. has been chemically modifying existing aminoglycosides in a systematic manner in order to work round resistance.

The first fruits of this endeavour, a 'neoglycoside', recently came through a highly successful phase I trial.

Aminoglycosides are broad-spectrum antibiotics. Achaogen's principal targets are multidrug-resistant Gram-negative bacteria, including intestinal pathogens such as E. coli, Pseudomonas aeruginosa and MRSA.

Aminoglycosides are complex organic molecules produced by a range of bacteria. Although highly effective, their use is being curtailed by the development of resistance. To maintain their efficacy, Achaogen has made a range of chemical modifications to the sites on the molecules known to be targeted by resistance mechanisms. Preclinical studies have shown that this is a successful strategy for overcoming resistance while maintaining the agents' antibacterial properties.

In the phase I trial, the safety of the leading candidate was tested in a small randomised placebo-controlled trial. No ill-effects were seen, paving the way for phase II trials in 2010, starting with complicated urinary tract infections.

There is reason to be optimistic that neoglycosides will overcome the hurdles of phase II and III trials. For antibiotics, the jump from animal to human studies is not so great, as the target - the bacterium - is the same in both cases. Moreover, a great deal is already known about the safety and effectiveness of aminoglycosides, which will be relevant to the development of their relatives.

The results of the phase I trial were released at the 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Annual Meeting in San Francisco, September 2009.

Image: MRSA, an important target for neoglycosides