Abstract：
:With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Song D,Zhang N,Zhang P,Zhang N,Chen W,Zhang L,Guo T,Gu X,Ma Sdoi
10.1016/j.ejmech.2021.113480keywords:
["9-Arylalkyl-10-methylacridinium derivatives","Antibacterial activity","Design and synthesis","FtsZ inhibitor","Structure-activity relationships"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113480eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00329-9journal_volume
221pub_type
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