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ABSTRACT
The rapid proliferation of multidrug-resistant (MDR) bacterial pathogens poses a serious threat to healthcare worldwide. Carbapenem-resistant (CR) Enterobacteriaceae, which have near-universal resistance to available antimicrobials, represent a particularly concerning issue. Herein, we report the identification of AMXT-1501, a polyamine transport system inhibitor with antibacterial activity against Gram-positive and -negative MDR bacteria. We observed minimum inhibitory concentration (MIC)50/MIC90 values for AMXT-1501 in the range of 3.13–12.5 μM (2.24–8.93 μg /mL), including for methicillin-resistant Staphylococcus aureus (MRSA), CR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. AMXT-1501 was more effective against MRSA and CR E. coli than vancomycin and tigecycline, respectively. Subinhibitory concentrations of AMXT-1501 reduced the biofilm formation of S. aureus and Enterococcus faecalis. Mechanistically, AMXT-1501 exposure damaged microbial membranes and increased membrane permeability and membrane potential by binding to cardiolipin (CL) and phosphatidylglycerol (PG). Importantly, AMXT-1501 pressure did not induce resistance readily in the tested pathogens.
Acknowledgments
The authors would like to thank Prof. Jin-Town Wang and Ph.D. Zhi-Rong Lin (Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan, and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan) for generously providing the K. pneumoniae NTUH-K2044 strain. The authors also thank Weiguang Pan and Jie Lian (Department of Laboratory Medicine, Shenzhen Nanshan People’s Hospital and the 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen 518052, China) for helping identify and preserve the bacterial strains.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The raw whole-genome sequencing data was posted in the Sequence Read Archive (SRA) database under accession number PRJNA1007457 (http://www.ncbi.nlm.nih.gov/bioproject/1007457). All the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding authors upon reasonable request. A reporting summary for this article is available as a Supplementary Information file.
Author contributions
Z.J.Y., and Z.W.W. conceived and designed the project. J.X.Z., J.X.L., Y.P.X., Q.Y.M., F.Z., and X.M.L. performed experiments. P.Y.L., Z.W.L., and Q.W.D. analyzed data. J.X.Z., and Z.J.Y. wrote and finalized the manuscript. All authors read and approved the manuscript.
Ethics approval and consent to participate
All bacteria collections were performed in accordance with the ethical standards of Shenzhen Nanshan People’s Hospital and the 6th Affiliated Hospital of Shenzhen University Medical School and with the 1964 Helsinki declaration and its amendments. This study was approved by the ethics committee of the Shenzhen Nanshan People’s Hospital and the 6th Affiliated Hospital of Shenzhen University Medical School. Isolates were collected as part of routine clinical management according to national guidelines in China. Therefore, informed consent was not required or sought.
The mice experiments were approved by the Committee of Shenzhen Nanshan People’s Hospital and the 6th Affiliated Hospital of Shenzhen University Medical School, and by the Animal Ethics of the Ethics Committee of Shenzhen University Medical School.