Antimicrobial peptide exposure selects forStaphylococcus aureusresistance to human defence peptides

Abstract

BackgroundThe clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in MDR bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system and the ramifications of prolonged bacterial exposure to AMPs are not fully understood.ObjectivesWe show that in vitro serial passage of a clinical USA300 MRSA strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP resistance.MethodsSerial passage experiments were conducted using steadily increasing concentrations of LL-37, PR-39 or wheat germ histones. WGS and proteomic analysis by MS were used to identify the molecular mechanism associated with increased tolerance of AMPs. AMP-resistant mutants were characterized by measuring in vitro fitness, AMP and antibiotic susceptibility, and virulence in a mouse model of sepsis.ResultsAMP-resistant Staphylococcus aureus mutants often displayed little to no fitness cost and caused invasive disease in mice. Further, this phenotype coincided with diminished susceptibility to both clinically prescribed antibiotics and human defence peptides.ConclusionsThese findings suggest that therapeutic use of AMPs could select for virulent mutants with cross-resistance to human innate immunity as well as antibiotic therapy. Thus, therapeutic use of AMPs and the implications of cross-resistance need to be carefully monitored and evaluated.

Genomic signature of experimental adaptation of Staphylococcus aureus to a natural combination of insect antimicrobial peptides

“…At the moment it is not clear why the more costly double-mutation evolves, given that there is no difference in MICs between nsa and nsa/rpoB mutants. Limited costs in S. aureus selected for resistance against the human AMP LL-37 were reported 35 , but the same study found reduced growth rates in AMP-resistant strains. Antibiotic resistance evolution resulting in extended lag phases has been frequently reported (e.g.…”

“…With the exception of the double mutation nsa/rpoB , which displays the longest lag phase the costs in our experiments do not segregate by mutation. rpoB mutations in AMP-resistant S. aureus have been found before 35 . At the moment it is not clear why the more costly double-mutation evolves, given that there is no difference in MICs between nsa and nsa/rpoB mutants.…”

Antifungal peptides: Biosynthesis, production and applications

“…Syringostantin A had MIC of 5.0μg/ ml against A. fumigatus. Syringotoxin B had MIC of 3.2μg/ml against C. albicans (Sorensen et al, 1996;Zhao et al, 2013;Chereddy et al, 2014;Deslouches et al, 2015;Gao et al, 2016;Kubicek-Sutherland et al, 2017).…”

Making plants into cost-effective bioreactors for highly active antimicrobial peptides

“…Thousands of AMPs have been isolated and tested experimentally (Wang et al , 2015) and many more can be discovered using algorithms to scan genome data bases (Islam et al , 2018b). Second, though resistance to AMPs has been shown to develop in bacteria (Kubicek-Sutherland et al ., 2017), the multiple antimicrobial activities and low affinity targets typical of AMPs have been thought to make them more difficult targets for resistance development by pathogenic bacteria (Peschel and Sahl, 2006). From an environmental perspective, AMPs are not long-lasting in waste water, whereas low concentrations of antibiotics can induce resistance in soil and water-borne microbial communities (Bengtsson-Palme et al, 2018).…”