Structure-activity relationships and optimization of acyclic acylphloroglucinol analogues as novel antimicrobial agents.
Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to global public health, because it exhibits resistance to existing antibiotics and therefore high rates of morbidity and mortality. In this study, twenty-one natural product-based acylphloroglucinol congeners were synthesized, which possessed different side chains. Antibacterial screening against MRSA strains revealed that acyl moiety tailoring is a prerequisite for the antibacterial activity. Moreover, the lipophilicity, rather than the magnitude of the hydrophobic acyl tail dominates variability in activity potency. Compound 11j was identified as a promising lead for the generation of new anti-MRSA drug development. It was discovered by optimization of the side chain length in light of the potency, the breadth of the antibacterial spectrum, the rate of bactericidal action, as well as the membrane selectivity. Compound 11j exerted profound in vitro antibacterial activity against the MRSA strain (JCSC 2172), and its MIC was 3-4 orders of magnitude lower than that of vancomycin. A preliminary mode of action study of compound 11j at the biophysical and morphology levels disclosed that the mechanism underlying its anti-MRSA activity included membrane depolarization and, to a lesser extent, membrane disruption and cell lysis.
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China.
Haibo
H
Tan
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China; State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, People's Republic of China.
Hongxin
H
Liu
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Liyun
L
Zhao
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Yao
Y
Yuan
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Bailin
B
Li
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China.
Yueming
Y
Jiang
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China. Electronic address: lianggong@scbg.ac.cn.
Liang
L
Gong
Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People's Republic of China. Electronic address: sxqiu@scbg.ac.cn.
Shengxiang
S
Qiu
D000215:Acylation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D010696:Phloroglucinol
Acylphloroglucinol; Anti-MRSA; Mechanism; Structure-activity relationship