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Applied and environmental microbiology
05 24, 2022;88 (10): e0037122.

Plantaricin A, Derived from Lactiplantibacillus plantarum, Reduces the Intrinsic Resistance of Gram-Negative Bacteria to Hydrophobic Antibiotics.

Fanqiang Meng, Yanan Liu, Ting Nie, Chao Tang, Fengxia Lyu, Xiaomei Bie, Yingjian Lu, Mingwen Zhao, Zhaoxin Lu
Author Information
  1. Fanqiang Meng: College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China. ORCID
  2. Yanan Liu: College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China.
  3. Ting Nie: School of Life Sciences and Biotechnology, Shanghai Jiao Tong Universitygrid.16821.3c, Shanghai, People's Republic of China.
  4. Chao Tang: College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China.
  5. Fengxia Lyu: College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China.
  6. Xiaomei Bie: College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China. ORCID
  7. Yingjian Lu: College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing, Jiangsu, People's Republic of China.
  8. Mingwen Zhao: Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture, Department of Microbiology, College of Life Sciences, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China. ORCID
  9. Zhaoxin Lu: College of Food Science and Technology, Nanjing Agricultural Universitygrid.27871.3b, Nanjing, Jiangsu, People's Republic of China. ORCID
PMID: 35499329 DOI: 10.1128/aem.00371-22

Abstract

The outer membrane of Gram-negative bacteria is one of the major factors contributing to the development of antibiotic resistance, resulting in a lack of effectiveness of several hydrophobic antibiotics. Plantaricin A (PlnA) intensifies the potency of antibiotics by increasing the permeability of the bacterial outer membrane. Moreover, it has been proven to bind to the lipopolysaccharide of Escherichia coli via electrostatic and hydrophobic interactions and to interfere with the integrity of the bacterial outer membrane. Based on this mechanism, we designed a series of PlnA1 analogs by changing the structure, hydrophobicity, and charge to enhance their membrane-permeabilizing ability. Subsequent analyses revealed that among the PlnA1 analogs, OP4 demonstrated the highest penetrating ability, weaker cytotoxicity, and a higher therapeutic index. In addition, it decelerated the development of antibiotic resistance when the E. coli cells were continuously exposed to sublethal concentrations of erythromycin and ciprofloxacin for 30 generations. Further studies in mice with sepsis showed that OP4 heightens the potency of erythromycin against E. coli and relieves inflammation. In summary, our results showed that the PlnA1 analogs investigated in the present study, especially OP4, reduce the intrinsic antibiotic resistance of Gram-negative pathogens and expand the antibiotic sensitivity spectrum of hydrophobic antibiotics in Gram-negative bacteria. Antibiotic resistance is a global health concern due to indiscriminate use of antibiotics, resistance transfer, and intrinsic resistance of certain Gram-negative bacteria. The asymmetric bacterial outer membrane prevents the entry of hydrophobic antibiotics and renders them ineffective. Consequently, these antibiotics could be employed to treat infections caused by Gram-negative bacteria, after increasing their outer membrane permeability. As PlnA reportedly penetrates outer membranes, we designed a series of PlnA1 analogs and proved that OP4, one of these antimicrobial peptides, effectively augmented the permeability of the bacterial outer membrane. Furthermore, OP4 effectively improved the potency of erythromycin and alleviated inflammatory responses caused by Escherichia coli infection. Likewise, OP4 curtailed antibiotic resistance development in E. coli, thereby prolonging exposure to sublethal antibiotic concentrations. Thus, the combined use of hydrophobic antibiotics and OP4 could be used to treat infections caused by Gram-negative bacteria by decreasing their intrinsic antibiotic resistance.

Keywords

E. coli antibacterial mechanism antibiotic resistance antimicrobial peptide outer membrane sepsis

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MeSH Term

Animals
Anti-Bacterial Agents
Bacteriocins
Drug Resistance, Bacterial
Erythromycin
Escherichia coli
Escherichia coli Infections
Gram-Negative Bacteria
Hydrophobic and Hydrophilic Interactions
Mice
Microbial Sensitivity Tests

Chemicals

Anti-Bacterial Agents
Bacteriocins
plantaricin A
Erythromycin
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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