Brevicidine acts as an effective sensitizer of outer membrane-impermeable conventional antibiotics for Acinetobacter baumannii treatment

Xinyi Zhong; Kai Deng; Xiuhan Yang; Xu Song; Yuanfeng Zou; Xun Zhou; Huaqiao Tang; Lixia Li; Yuping Fu; Zhongqiong Yin; Hongping Wan; Xinghong Zhao

doi:10.3389/fmicb.2023.1304198

Brevicidine acts as an effective sensitizer of outer membrane-impermeable conventional antibiotics for Acinetobacter baumannii treatment

Front Microbiol. 2023 Dec 15:14:1304198. doi: 10.3389/fmicb.2023.1304198. eCollection 2023.

Authors

Xinyi Zhong^#^{1

2}, Kai Deng^#^{2

3}, Xiuhan Yang^#^{1

2}, Xu Song^{1

2}, Yuanfeng Zou^{1

2}, Xun Zhou^{1

2}, Huaqiao Tang^{1

2}, Lixia Li^{1

2}, Yuping Fu^{1

2}, Zhongqiong Yin^{1

2}, Hongping Wan^{2

3}, Xinghong Zhao^{1

2

3}

Affiliations

¹ Center for Sustainable Antimicrobials, Department of Pharmacy, Sichuan Agricultural University, Chengdu, China.
² Center for Infectious Diseases Control (CIDC), Sichuan Agricultural University, Chengdu, China.
³ Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.

^# Contributed equally.

Abstract

The antibiotic resistance of Acinetobacter baumannii poses a significant threat to global public health, especially those strains that are resistant to carbapenems. Therefore, novel strategies are desperately needed for the treatment of infections caused by antibiotic-resistant A. baumannii. In this study, we report that brevicidine, a bacterial non-ribosomally produced cyclic lipopeptide, shows synergistic effects with multiple outer membrane-impermeable conventional antibiotics against A. baumannii. In particular, brevicidine, at a concentration of 1 μM, lowered the minimum inhibitory concentration of erythromycin, azithromycin, and rifampicin against A. baumannii strains by 32-128-fold. Furthermore, mechanistic studies were performed by employing erythromycin as an example of an outer membrane-impermeable conventional antibiotic, which showed the best synergistic effects with brevicidine against the tested A. baumannii strains in the present study. The results demonstrate that brevicidine disrupted the outer membrane of A. baumannii at a concentration range of 0.125-4 μM in a dose-dependent manner. This capacity of brevicidine could help the tested outer membrane-impermeable antibiotics enter A. baumannii cells and thereafter exert their antimicrobial activity. In addition, the results show that brevicidine-erythromycin combination exerted strong A. baumannii killing capacity by the enhanced inhibition of adenosine triphosphate biosynthesis and accumulation of reactive oxygen species, which are the main mechanisms causing the death of bacteria. Interestingly, brevicidine and erythromycin combination showed good therapeutic effects on A. baumannii-induced mouse peritonitis-sepsis models. These findings demonstrate that brevicidine is a promising sensitizer candidate of outer membrane-impermeable conventional antibiotics for treating A. baumannii infections in the post-antibiotic age.

Keywords: Acinetobacter baumannii; antibiotic-resistant; bacteraemia model; brevicidine; synergistic effects.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the “1000-Talent Program” in Sichuan Province [XZha (2287) and HW (1923)]. XZha was supported by the Science and Technology Project of Sichuan Province (2022YFH0057). HW was supported by the National Natural Science Foundation of China (32102689) and the Science and Technology Project of Sichuan Province (2022YFH0062, 2022ZYD0068).