Genomic Insights into Bacterial Resistance to Proline-Rich Antimicrobial Peptide Bac7

• Published in: Membranes (Basel) Vol. 13; no. 4; p. 438
• Main Authors: Panteleev, Pavel V, Safronova, Victoria N, Kruglikov, Roman N, Bolosov, Ilia A, Ovchinnikova, Tatiana V
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-04-2023; MDPI
• Subjects: Amino acid substitution; Amino acids; Analysis; antibiotic; Antibiotics; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; antimicrobial peptide; Antimicrobial peptides; Bac7; bacterial resistance; cathelicidin; Causes of; Cross-resistance; Drug development; Drug resistance in microorganisms; E coli; Genetic aspects; Genomes; Heptose; Inactivation; Kinases; Mammalian cells; Medical research; Multidrug resistance; Mutation; Pathogens; Peptides; Phenotypes; Phosphorylation; Point mutation; Polymyxin B; Proline; proline-rich peptide; Properties; Proteins; Strains (organisms); Toxicity; Urinary tract; Russia; St Louis Missouri; United States > US; Germany; antibiotic; cathelicidin; bacterial resistance; SbmA transporter; WaaP kinase; proline-rich peptide; Bac7; antimicrobial peptide; LPS
• ISSN: 2077-0375; 2077-0375
• DOI: 10.3390/membranes13040438

Proline-rich antimicrobial peptides (PrAMPs) having a potent antimicrobial activity and a modest toxicity toward mammalian cells attract much attention as new templates for the development of antibiotic drugs. However, a comprehensive understanding of mechanisms of bacterial resistance development to PrAMPs is necessary before their clinical application. In this study, development of the resistance to the proline-rich bovine cathelicidin Bac7
derivative was characterized in the multidrug-resistant
clinical isolate causing the urinary tract infection. Three Bac7
-resistant strains with ≥16-fold increase in minimal inhibitory concentrations (MICs) were selected by serially passaging after four-week experimental evolution. It was shown that in salt-containing medium, the resistance was mediated by inactivation of the SbmA transporter. The absence of salt in the selection media affected both dynamics and main molecular targets under selective pressure: a point mutation leading to the amino acid substitution N159H in the WaaP kinase responsible for heptose I phosphorylation in the LPS structure was also found. This mutation led to a phenotype with a decreased susceptibility to both the Bac7
and polymyxin B. Screening of antimicrobial activities with the use of a wide panel of known AMPs, including the human cathelicidin LL-37 and conventional antibiotics, against selected strains indicated no significant cross-resistance effects.