Introduction: Trimethoprim (TMP) and sulfamethoxazole (SMX) have been widely used in combination to treat infections for over 60 years. Both drugs target adjacent steps of the folate synthesis pathway, mutually potentiating each other’s effects and leading to enhanced killing. While this combination is used in clinical practice due to the strong synergy between component drugs, antibiotic interactions can be species and even strain specific, potentially leading to treatment failure. Despite the clinical implications of this specificity, the molecular mechanisms driving species- and strain-specific drug interactions remain largely unexplored.
Objectives: The goal of this work was to characterise how TMP-SMX can interact against the clinically important pathogen, Acinetobacter baumannii, with the aim of predicting the interaction in different strains based on specific phenotypic or genotypic traits.
Methods: We conducted dose-response curve matrix experiments to characterise the interaction landscape of TMP-SMX across a diverse, international collection of A. baumannii strains. We then used mutant phenotypic assays to explore the role of specific resistance genes in modulating the different TMP-SMX interactions observed across our strains.
Results and Conclusions: We found that TMP and SMX can interact both additively and synergistically in A. baumannii. Additivity was generally predictable based on the presence of either trimethoprim (dfr) or sulfonamide (sul) resistance genes. However, this trend was not absolute, and different sul gene variants modulated the drug interaction differently. We also found that the type of interaction was influenced by RND efflux pumps, though the impact of specific pumps varied between strains. We confirmed that the interaction of TMP and SMX in A. baumannii could be altered from additive to synergistic and vice versa by altering resistance gene composition. Overall, our findings underscore the complexity of antibiotic interactions and resistance in A. baumannii and suggest that TMP-SMX therapy could be optimised based on resistance gene profiling.