Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis HIV infections or malignancy. the component drugs. Then using designed strains we confirmed that drug resistance mutations that imposed AV-412 collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance development. INTRODUCTION Bacteria inevitably evolve antibiotic resistance in response to prolonged exposure to drugs; consequently antibiotic resistance always follows the introduction of new antibiotics (1)-a pattern that has led to the emergence of virtually untreatable multidrug-resistant bacteria such as extensively drug-resistant tuberculosis and carbapenem-resistant and strains (2 3 Drug resistance evolves either through horizontal acquisition of resistance genes or through mutations in the bacterial genome. In the latter case the length of treatment and patient compliance greatly influence resistance development because prolonged subinhibitory drug concentrations select for resistant bacteria (4). A similar pattern applies to viral resistance which evolves quickly because of a high large quantity of viral particles in the host and the high error rate associated with viral replication (5). One approach to counteract drug resistance development in bacteria and viruses is with combination drug therapy. This approach first proved its success in the late 1940s when the combination AV-412 of streptomycin and para-aminosalicylic acid was shown to markedly reduce development of resistant compared to streptomycin monotherapy (6). Similarly the use of combination therapy to treat HIV infections has been successful in reducing drug resistance resulting in increased life expectancy of HIV patients (7). Furthermore combination therapy is Rabbit polyclonal to PLAT. being used to combat drug resistance in malignancy which like tuberculosis requires months-long treatment with chemotherapeutic brokers (8). Other reasons for using drug combinations include synergistic therapeutic effects and increased spectrum of activity (9). Thus the search for synergy has dominated the field of antimicrobial combination treatments for many decades with successful examples including the sulfamethoxazole-trimethoprim combination and simultaneous treatment with a ��-lactam antibiotic and a ��-lactamase inhibitor (10-12). Synergy however can have two conflicting effects on resistance: it reduces development of resistance because it clears the infection faster thereby limiting the time windows available for resistant mutations to arise but it also increases the selective advantage of single drug-resistant mutants (13). When competition for resources is strong the latter effect can dominate (13); indeed under these conditions drug combinations that are antagonistic (that is when the combination is less potent than the sum of its components) have been shown to limit development of AV-412 resistance (14-16). The advantage of antagonistic combinations over synergistic combinations is the result of a reduced fitness gain when bacteria develop resistance to antagonistic combinations compared to developing resistance to synergistic combinations (14-16). In addition to drug interactions (synergy and antagonism) collateral sensitivity among the drugs is also believed to play a major role AV-412 in driving the development of resistance against drug combinations. Collateral sensitivity and resistance also known as cross-resistance occurs when mutations conferring resistance to one drug increase or decrease sensitivity to another drug. The study of collateral susceptibility changes was pioneered by Szybalski and Bryson in the early 1950s and has since been reported for many different drugs and bacterial species as well as for virus malignancy cell lines and plants (17-28). We have recently shown that collateral sensitivity can be used to rationally design drug cycling regimens that limit the development AV-412 of resistance (29). Although the combined impact of both drug interactions and cross-resistance on selection in multidrug environments has been evaluated (16) it remains unclear which of.