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

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.