Abstract
Natural lipopeptide antibiotic tripropeptin C (TPPC) revitalizes and synergistically potentiates the activities of the class of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) but not against methicillin-sensitive S. aureus in vitro; however, the mode of action remains unclear. In the course of the study to reveal its mode of action, we found that TPPC inhibited the β-lactamase production induced by cefotiam. This prompted us to focus on the β-lactam-inducible β-lactam-resistant genes blaZ (β-lactamase) and mecA (foreign penicillin-binding protein), as they are mutually regulated by the blaZ/I/R1 and mecA/I/R1 systems. Quantitative reverse-transcription polymerase chain reaction analysis revealed that TPPC reversed β-lactam resistance by reducing the expression of the genes blaZ and mecA, when treated alone or in combination with β-lactam antibiotics. In a mouse/MRSA septicemia model, subcutaneous injection of a combination of TPPC and ceftizoxime demonstrated synergistic therapeutic efficacy compared with each drug alone. These observations strongly suggested that reverse β-lactam resistance by TPPC may be a potentially effective new therapeutic strategy to overcome refractory MRSA infections.
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Acknowledgements
The authors greatly appreciate the valuable advice from Prof Akio Nomoto and Dr Yoshimasa Ishizaki and the technical support from Shigeko Harada and Akiko Harakawa at the Institute of Microbial Chemistry (BIKAKEN, Japan).
This work was supported by the Japan Society for the Promotion of Science KAKENHI, grant numbers 24710254 and 16K08338.
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This article is dedicated to Prof. Hamao Umezawa on the occasion of the 60th anniversary of worldwide marketing of kanamycin.
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Hashizume, H., Takahashi, Y., Masuda, T. et al. In vivo efficacy of β-lactam/tripropeptin C in a mouse septicemia model and the mechanism of reverse β-lactam resistance in methicillin-resistant Staphylococcus aureus mediated by tripropeptin C. J Antibiot 71, 79–85 (2018). https://doi.org/10.1038/ja.2017.88
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DOI: https://doi.org/10.1038/ja.2017.88
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