Infectious diseases have recently attracted considerable attention on the LeadDiscovery website. This is because the anti-infectives market is poised to experience considerable growth in the next few years, with a forecast market value that is expected to double in size to more than $44 billion by 2010. This whole area is overviewed in one of our recently featured reports "Anti-Infectives 2002" (click here for access).

Intracellular bacteria and mycobacteria are particularly difficult to treat and as a result conditions such as Tuberculosis (Mycobacterium tuberculosis), listeriosis (Listeria monocytogenes), bacillary dysentery (Shigella dysenteriae) and legionnaires disease (Legionella pneumophila) can pose serious clinical challenges. Listeria and shigella are generally self-limiting and are therefore usually treated with supportive therapy. Legionnaires disease and tuberculosis represent a greater problem. Legionnaires' Disease accounts for 1 to 8% of community-acquired pneumonias that result in hospitalization and about 4% of lethal nosocomial pneumonias. Even with appropriate treatment, mortality is at least 15% in community-acquired cases and is higher among immunosuppressed or hospitalized patients.

About 10 million Americans are infected with Mycobacterium although only about 10% of these individuals will develop tuberculosis in their lifetime. Globally, tuberculosis is an increasing problem, especially in Africa where AIDS facilitates the spread. It is estimated that nearly 1 billion people will become infected, 200 million will become sick, and 70 million will die worldwide between now and 2020. In 1999, approximately 8.4 million cases and 2 million deaths were attributed to tuberculosis; 100,000 of those 2 million deaths occurred among children. One particular problem associated with tuberculosis is drug resistance and since mycobacterium are intracellular the risk is that treatments with poor access to intracellular reservoirs may only partially clear the pathogen allowing the development of drug-resistant strains. Developing strategies that allow the concentration of antibiotics within myobacterial reservoirs would be of considerable use

P-glycoprotein has received most attention with respect to cancer since it is responsible, in part, for drug resistance associated with many anti-cancer treatments. More recently, data has suggested that p-glycoprotein is also involved in the passage of molecules across the blood brain barrier and in the survival of inflammatory cells. The development of substrates or inhibitors of this protein therefore represents an active area of the pharmaceutical industry. Indeed over 15 molecules are in development, over half of which are in preclinical phases of evaluation.

Most recently, researchers at the Universite Catholique de Louvain in Belgium have demonstrated that the net influx rates of the macrolides azithromycin and telithromycin into macrophages were increased from 2- to 3.5-fold in the presence of a variety of p-glycoprotein inhibitors while their efflux was marginally slowed. At 3 h, the inhibitors increased the levels of azithromycin, erythromycin and telithromycin accumulation approximately three- to fourfold. The inhibitors also had an intermediate effect on roxithromycin accumulation. The exact mechanism underlying this phenomenon is unclear however the use of p-glycoprotein inhibitors alongside macrolide therapy could result in more effective treatment of tuberculosis and a reduced risk of drug resistance.

Adapted from Seral et al, Antimicrob Agents Chemother 2003 Mar;47(3):1047-51- Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk