Drug resistance is now becoming a major public health problem with acronyms such as MRSA entering the lexicon. The strategy we use here to combat resistance is to develop drug leads that have multiple targets. It is well known that many of the more successful drugs used in mono-therapy have more than one target, while drugs that are used in combination therapies have single targets and are often quite susceptible to single-point mutations leading to resistance in mono-therapy. This multi-targeting will reduce the occurrence of spontaneous drug resistance since more than one target would have to mutate. With this strategy, we have identified multi-targeting drug leads which simultaneously inhibit two key enzymes involved in isoprenoid (and hence, cell wall) biosynthesis: farnesyl diphosphate synthase (FPPS) and undecaprenyl diphosphate synthase (UPPS). We also find that the most potent anti-bacterial compounds we have developed so far (active in mice) also bind strongly to AT-rich DNA, and we have obtained X-ray structures showing minor-groove binding. This multiple-targeting/combination therapy concept is particularly suitable for targeting cell wall biosynthesis in bacteria since FPPS makes the product (FPP) used by UPPS, and methicillin and vancomycin target more downstream targets, opening up great possibilities for synergistic interactions � reducing resistance as well as, perhaps, dosings of more toxic antibiotics like vancomycin.

Combating drug resistance via multi-targeting

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.