The Anti-Multidrug-Resistant <i>Acinetobacter baumannii</i> Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds
Han Wu,
Hongtong Chen,
Jungan Zhang,
Xinxin Hu,
Chunyang Xie,
Weiting Cao,
Ziqi Zhao,
Zengshuo Xiao,
Yixin Ren,
Luyao Dong,
Peiyi Sun,
Xuefu You,
Xinyi Yang,
Wei Hong,
Hao Wang
Affiliations
Han Wu
School of Pharmacy, Minzu University of China, Beijing 100081, China
Hongtong Chen
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Jungan Zhang
School of Pharmacy, Minzu University of China, Beijing 100081, China
Xinxin Hu
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Chunyang Xie
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Weiting Cao
School of Pharmacy, Minzu University of China, Beijing 100081, China
Ziqi Zhao
School of Pharmacy, Minzu University of China, Beijing 100081, China
Zengshuo Xiao
School of Pharmacy, Minzu University of China, Beijing 100081, China
Yixin Ren
School of Pharmacy, Minzu University of China, Beijing 100081, China
Luyao Dong
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Peiyi Sun
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Xuefu You
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Xinyi Yang
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Wei Hong
Jingjinji National Center of Technology Innovation, Beijing 100094, China
Hao Wang
School of Pharmacy, Minzu University of China, Beijing 100081, China
As a major public health problem, the prevalence of Acinetobacter baumannii (A. baumannii) 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 Escherichia coli dihydrofolate reductase (ecDHFR), 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 A. baumannii DHFR (abDHFR)-inhibitors as well, which inspired us to consider their anti-A. baumannii abilities. We further found that three PQZ compounds, OYYF-171, -172, and -175, showed significant antibacterial activities against A. baumannii, 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 A. baumannii.
