Abstract
Most skin infections, including those complicating burns, are polymicrobial involving multiple causative bacteria. Add to this the fact that many of these organisms may be antibiotic-resistant, and a simple skin lesion or burn could soon become life-threatening. Membrane-acting cationic peptides from Gram-negative bacteriophage lysins can potentially aid in addressing the urgent need for alternative therapeutics. Such peptides natively constitute an amphipathic region within the structural composition of these lysins and function to permit outer membrane permeabilization in Gram-negative bacteria when added externally. This consequently allows the lysin to access and degrade the peptidoglycan substrate, resulting in rapid hypotonic lysis and bacterial death. When separated from the lysin, some of these cationic peptides kill sensitive bacteria more effectively than the native molecule via both outer and cytoplasmic membrane disruption. In this study, we evaluated the antibacterial properties of a modified cationic peptide from the broad-acting lysin PlyPa01. The peptide, termed PaP1, exhibited potent in vitro bactericidal activity toward numerous high priority Gram-positive and Gram-negative pathogens, including all the antibiotic-resistant ESKAPE pathogens. Both planktonic and biofilm-state bacteria were sensitive to the peptide, and results from time-kill assays revealed PaP1 kills bacteria on contact. The peptide was bactericidal over a wide temperature and pH range and could withstand autoclaving without loss of activity. However, high salt concentrations and complex matrices were found to be largely inhibitory, limiting its use to topical applications. Importantly, unlike other membrane-acting antimicrobials, PaP1 lacked cytotoxicity toward human cells. Results from a murine burn wound infection model using methicillin-resistant Staphylococcus aureus or multidrug-resistant Pseudomonas aeruginosa validated the in vivo antibacterial efficacy of PaP1. In these studies, the peptide enhanced the potency of topical antibiotics used clinically for treating chronic wound infections. Despite the necessity for additional preclinical drug development, the collective data from our study support PaP1 as a potential broad-spectrum monotherapy or adjunctive therapy for the topical treatment of polymicrobial infections and provide a foundation for engineering future lysin-derived peptides with improved antibacterial properties.
Highlights
Chronic wound infections are generally polymicrobial in nature (Bowler et al, 2001; Kirketerp-Moller et al, 2008)
The initial peptide candidates evaluated were derived from the P. aeruginosa lysin PlyPa01, which consists of 143 aa that encode a single muramidase domain
We propose using membrane-acting cationic peptides originating from highly evolved GN phage lysins as alternative therapeutics for treating topical bacterial infections
Summary
Chronic wound infections are generally polymicrobial in nature (Bowler et al, 2001; Kirketerp-Moller et al, 2008). The interactions between the different microorganisms in these diverse communities have significant ramifications on disease progression and clinical outcome, with higher mortality rates observed than monomicrobial infections due to increased pathogenicity, biofilm formation and antibiotic resistance (Short et al, 2014; Nabb et al, 2019). The increased prevalence of antibiotic resistance in these microenvironments has been selected for by drug overuse and misuse, which is a reality that poses a serious threat to global public health (Ventola, 2015). In the United States, there are more than 2.8 million antibiotic-resistant infections annually, resulting in over 35,000 deaths (Centers for Disease Control and Prevention, 2019). The absence of a coordinated discovery platform over the past 50 years has afforded bacteria the opportunity to continually develop resistance to existing antibiotics. The absence of effective antibiotics would have serious implications on medical procedures, such as surgery, dialysis, chemotherapy and organ transplantation (Lewis, 2020)
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