Characterizing the Antimicrobial Activity of ,-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii.

We previously reported a series of ,-disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potent and antibacterial activity against methicillin-resistant (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen We determined that optimized ,-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 μM, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LDs) of ≤23 μM for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellent efficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model of infection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg). Together, our results demonstrate that ,-disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.