The antimicrobial peptide DGL13K is active against drug-resistant gram-negative bacteria and sub-inhibitory concentrations stimulate bacterial growth without causing resistance

Abstract

Antimicrobial peptides may be alternatives to traditional antibiotics with reduced bacterial resistance. The antimicrobial peptide GL13K was derived from the salivary protein BPIFA2. This study determined the relative activity of the L-and D-enantiomers of GL13K to wild-type and drug-resistant strains of three gram-negative species and against Pseudomonas aeruginosa biofilms. DGL13K displayed in vitro activity against extended-spectrum beta-lactamase (ESBL)-producing and Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (MICs 16–32 μg/ml), MDR and XDR P. aeruginosa, and XDR Acinetobacter baumannii carrying metallo-beta-lactamases (MICs 8–32 μg/ml). P. aeruginosa showed low inherent resistance to DGL13K and the increased metabolic activity and growth caused by sub-MIC concentrations of GL13K peptides did not result in acquired bacterial resistance. Daily treatment for approximately two weeks did not increase the MIC of DGL13K or cause cross-resistance between LGL13K and DGL13K. These data suggest that DGL13K is a promising antimicrobial peptide candidate for further development.

Resisting the resistance: The antimicrobial peptide DGL13K selects for small colony variants of Staphylococcus aureus that show increased resistance to its stereoisomer LGL13K, but not to DGL13K.

“…The Gram-negative bacteria P. aeruginosa are highly susceptible to both LGL13K and DGL13K, showing only a 2-4-fold difference in MIC between the two peptide isomers (24, 27, 28). In fact, in a serial peptide exposure experiment, the MIC only increased about 2-fold for LGL13K and this increase was not statistically significant, suggesting that the bacteria are not able to mount resistance to either peptide stereoisomer (27). To validate this finding, P. aeruginosa was serially exposed to LGL13K or DGL13K.…”

The oral pathogenPorphyromonas gingivalisresists the antimicrobial peptide LGL13K and evades the D-enantiomer by synonymous mutations inhagA

“…We have previously reported that three strains of P. gingivalis (W50, ATCC 53977 and DPG3) are resistant to LGL13K but not to the endogenous antimicrobial peptide LL-37 (43). We have since designed an all-D amino acid version of this peptide (DGL13K) (53), which resists proteolytic degradation and kills both Gram negative and Gram positive bacteria (53)(54)(55)(56). Timed-kill assays showed that P. gingivalis W50 were killed by DGL13K but not LGL13K or polymyxin B (Fig.…”

Nano-based theranostic approaches for infection control: current status and perspectives

“…Apart from immunomodulators, AMPs, a class of peptides with diverse sequences and structures, offer several key advantages over antibiotics due to high potency, ability to tackle a broad spectrum of microbes, multiple modes of action and low risk of AMR development. [50][51][52][53] These peptides, particularly the ones with cationic or anionic charges, can disturb the membrane of bacteria, interrupt the enzyme activity, or interact with their intracellular components, causing apoptosis or necrosis through various models, depending on the bacterial strains. 54 Nonetheless, AMPs as therapeutic agents may be restricted due to their instability in physiological salt concentrations, susceptibility to protease degradation, hemolytic activity, inconsistency in their impacts on bacterial membranes and toxicity to mammalian cells.…”