CHEMICAL-CHEMICAL COMBINATIONS AS TOOLS OF BIOLOGY AND AS ROUTES TO DRUG DISCOVERY

Abstract

With dramatic rises in bacterial resistance both in the clinic and community, there is an urgent need for new chemical matter and strategies. Over the years, antibacterial drug discovery has been centered almost entirely on identifying single agents that target essential proteins or enzymes. Recent advances in systems biology have suggested that this paradigm may not be as therapeutically effective as combinations of drugs. Further, chemical-chemical combinations, rather than single agents, can be used to probe relationships between target proteins in a biological system, maximizing insight into its functional organization. In this regard, we first demonstrate that systematic testing of chemical-chemical combinations can yield information on the functional connections that exist among molecular targets. Indeed, chemical-chemical interaction profiles with various drug classes provided powerful means to elucidate the mode of action of two uncharted compounds active against E. coli. In fact, this approach proved invaluable as a method for target identification in all phenotype-based screening efforts that followed. Systematic testing of combinations of chemicals can also lead to the discovery of synergistic interactions with enhanced antibacterial activity. In this respect, two unique screening strategies were adopted to identify novel combinations effective against drug-resistant pathogens. The first uncovered ticlopidine, a novel adjuvant to β-lactam antibiotics that together, synergize against MRSA through an intricate mechanism involving the concerted synthesis of wall teichoic acid polymers and cell wall. The second screening approach identified unique synergistic combinations through a search for molecules that modulate each of the compensatory pathways that regulate bacterial proton motive force. This unconventional screening approach led to the identification of nine novel synergistic pairs effective against MRSA. Overall, this work illustrates the powerful capacity of chemical-chemical combinations as tools to probe mechanism of novel compounds and as routes to new drug discovery. Importantly, such combinatorial approaches at probing systems and targeting pathogens are consonant with the modern view of the cell.