Unveiling the antimicrobial action of MMV676501, MMV687807, and MMV102872 against Staphylococcus aureus: A mechanistic investigation

The urgent need for new antimicrobials combats the rising threat of resistant pathogens. To optimize lead compounds, understanding their mechanisms of action is crucial for target optimization and improved pharmacokinetics. We employed microarray analysis to investigate the impact of selected MMV compounds on the S. aureus transcriptome. Differential gene expression (DEG) analysis was performed following exposure to MMV 676501, MMV 687807, and MMV 102872. MMV 676501 treatment resulted in 26 DEGs (12 upregulated, 14 downregulated). Similarly, MMV 687807 and MMV 102872 treatments yielded 34 DEGs (11 upregulated, 23 downregulated) and 31 DEGs (18 upregulated, 13 downregulated), respectively. Pathway analysis revealed that MMV 676501 targets nitrogen metabolism, while MMV 102872 downregulates genes (purS, purC, lexA) involved in purine metabolism. MMV 687807 appears to affect multiple metabolic pathways. Our transcriptomic approach demonstrates the differential impact of MMV compounds on S. aureus. These results provide mechanistic insights, highlighting specific metabolic pathways affected by each compound. This knowledge is valuable for guiding future target optimization and improving the compounds’ pharmacological properties.