Azalomycin F4a targets peptidoglycan synthesis of Gram-positive bacteria revealed by high-throughput CRISPRi-seq analysis

Zhou，Yachun1,2; Song，Yue3,4; Zhang，Yu5; Liu，Xue5; Liu，Lei2; Bao，Yanmin6; Wang，Junfeng3,4; Yang，Liang1,2

2024-03-01

10.1016/j.micres.2023.127584

Microbiological Research   影响因子和分区

0944-5013

Azalomycin F4a is a promising 36-membered polyhydroxy macrolide that shows antibacterial activity against drug-resistant Gram-positive bacteria, but its exact working mechanism remains to be elusive. Here, we isolated the azalomycin F4a product from a Streptomyces solisilvae and demonstrated its antibacterial activity against Gram-positive pathogens including Streptococcus pneumoniae, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). We further showed that combination of azalomycin F4a with methicillin has an additive antimicrobial effect on MRSA, where the minimal inhibitory concentrations (MIC) of methicillin to MRSA was decreased by 1000-fold in the presence of sublethal concentration of azalomycin F4a. A CRISPRi-seq based whole genome screen was employed to identify the potential targets of azalomycin F4a, which revealed that peptidoglycan synthesis (PGS) was inhibited by azalomycin F4a. Furthermore, azalomycin F4a treatment could significantly impair S. aureus biofilm formation. Our research highlights that cell wall synthesis is an additional target for novel classes of macrolide besides ribosome.

Azalomycin F4a Biofilm CRISPRi-seq MRSA Peptidoglycan synthesis

EI

英语

第一 ; 通讯

MICROBIOLOGY

2-s2.0-85181122244

Scopus

1.School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
2.Shenzhen Third People's Hospital,National Clinical Research Centre for Infectious Disease,The Second Affiliated Hospital of Southern University of Science and Technology,Shenzhen,518112,China
3.CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica,South China Sea Institute of Oceanology,Chinese Academy of Sciences,Guangzhou,510301,China
4.University of Chinese Academy of Sciences,Beijing,100049,China
5.Department of Pathogen Biology,Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Centre,International Cancer Centre,Shenzhen University Health Science Centre,Shenzhen,518055,China
6.Department of Respiratory Diseases,Shenzhen Children's Hospital,Shenzhen,Guangdong,518031,China

Zhou，Yachun,Song，Yue,Zhang，Yu,et al. Azalomycin F4a targets peptidoglycan synthesis of Gram-positive bacteria revealed by high-throughput CRISPRi-seq analysis[J]. Microbiological Research,2024,280.

Zhou，Yachun.,Song，Yue.,Zhang，Yu.,Liu，Xue.,Liu，Lei.,...&Yang，Liang.(2024).Azalomycin F4a targets peptidoglycan synthesis of Gram-positive bacteria revealed by high-throughput CRISPRi-seq analysis.Microbiological Research,280.

Zhou，Yachun,et al."Azalomycin F4a targets peptidoglycan synthesis of Gram-positive bacteria revealed by high-throughput CRISPRi-seq analysis".Microbiological Research 280(2024).