The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-12, Vol.27 (23), p.8609
• Main Authors: Wu, Han, Chen, Hongtong, Zhang, Jungan, Hu, Xinxin, Xie, Chunyang, Cao, Weiting, Zhao, Ziqi, Xiao, Zengshuo, Ren, Yixin, Dong, Luyao, Sun, Peiyi, You, Xuefu, Yang, Xinyi, Hong, Wei, Wang, Hao
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Acinetobacter Infections - drug therapy; Amides; Amino acids; Aminoglycoside antibiotics; Aminoglycosides; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibacterial activity; Antibacterial agents; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bacteria; Dihydrofolate reductase; Dihydropteroate synthase; Drug resistance; Drug Resistance, Multiple, Bacterial; Enzymes; Folic acid; Folic Acid Antagonists - pharmacology; Humans; Inhibitors; Metabolism; Microbial Sensitivity Tests; Multidrug resistance; Multidrug resistant organisms; Nosocomial infections; Pathogens; Proteins; Public health; Quinazolines - pharmacology; Reductases; Simulation; Sulfamethoxazole; Synergistic effect; Tetrahydrofolate Dehydrogenase; Trimethoprim; Vitamin B; β-Lactam antibiotics
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27238609

As a major public health problem, the prevalence of ( ) infections in hospitals due to the pathogen's multiple-antibiotic resistance has attracted extensive attention. We previously reported a series of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQZ) compounds, which were designed by targeting dihydrofolate reductase ( DHFR), and exhibited potent antibacterial activities. In the current study, based on our molecular-modeling study, it was proposed that PQZ compounds may function as potent DHFR ( DHFR)-inhibitors as well, which inspired us to consider their anti- abilities. We further found that three PQZ compounds, OYYF-171, -172, and -175, showed significant antibacterial activities against , including multidrug-resistant (MDR) strains, which are significantly stronger than the typical DHFR-inhibitor, trimethoprim (TMP), and superior to, or comparable to, the other tested antibacterial agents belonging to β-lactam, aminoglycoside, and quinolone. The significant synergistic effect between the representative compound OYYF-171 and the dihydropteroate synthase (DHPS)-inhibitor sulfamethoxazole (SMZ) was observed in both the microdilution-checkerboard assay and time-killing assay, which indicated that using SMZ in combination with PQZ compounds could help to reduce the required dosage and forestall resistance. Our study shows that PQZ is a promising scaffold for the further development of folate-metabolism inhibitors against MDR .