Evaluation of Novel Meliodosis Therapeutics

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Abstract Burkholderia pseudomallei is the etiologic agent of melioidosis. This disease is endemic to tropical and subtropical regions of the world but is now considered an emerging disease, as well as a disease of biodefense importance. Because of B. pseudomallei's intrinsic resistance to many antibiotics, melioidosis therapy is difficult and, because of the tendency of the bacterium to become latent, must be continued for extended periods of time. The limited spectrum of antibiotics available for melioidosis treatment, and the emergence of resistant strains in endemic regions calls for development of new therapeutics. Furthermore, successful treatment of infections caused by bioterrorism events involving strains which have acquired additional resistance determinants, whether by natural means or by malicious genetic engineering, may be impossible without new therapeutics. We hypothesize that several new investigational drugs, some of which are in clinical trials, may also be efficacious against B. pseudomallei. Two specific aims will be pursued to test this hypothesis. In Aim 1, in vitro efficacies of BAL30072 (a monobactam), cethromycin (a ketolide) and iclaprim (a trimethoprim analog) will be assessed against a panel of >100 clinical and environmental isolates, establishing MIC90 values in the process and time-kill curves for each antibiotic for a subset of these isolates. Chromosomally encoded p-lactamase genes will be expressed and evaluated as potential BAL30072 resistance mechanisms. In aim 2, then, in vivo therapeutic efficacy of BAL30072, cethromycin and iclaprim will be assessed in a BALB/c mouse model of acute B. pseudomallei infection using proven melioidosis therapeutics as controls. As these investigational drugs are in Phase I through Phase III clinical trials for other indications, demonstration of in vitro and in vivo activity against B. pseudomallei will enable rapid advancement of these antimicrobials to experiments with non-human primates and into Phase I clinical trials. Public Health relevance. Closely related bacteria also cause difficult or impossible to cure infections and we believe that it is likely that the advances we made with B. pseudomallei therapeutics will be directly applicable to infections by other biothreat agents such as B. mallei and perhaps the emerging pathogen B. Cenocepacia