A peptide-morpholino oligomer conjugate targeting Staphylococcus aureus gyrA mRNA improves healing in an infected mouse cutaneous wound model

Abstract

Management of skin wound infections presents a serious problem in the clinic, in the community, and in both civilian and military clinical treatment centers. Staphylococcus aureus is one of the most common microbial pathogens in cutaneous wounds. Peptide-morpholino oligomer (PMO) conjugates targeted to S. aureus gyrase A mRNA have shown the ability to reduce bacterial viability by direct site-specific mRNA cleavage via RNase P. As a treatment, these conjugates have the added advantages of not being susceptible to resistance due to genetic mutations and are effective against drug resistant strains. While this strategy has proven effective in liquid culture, it has yet to be evaluated in an animal model of infected surface wounds. In the present study, we combined PMO conjugates with a thermoresponsive gel delivery system to treat full-thickness mouse cutaneous wounds infected with S. aureus. Wounds treated with a single dose of PMO conjugate displayed improved healing that was associated with increased epithelialization, reduced bacterial load, and increased matrix deposition. Taken together, our findings demonstrate the efficacy and flexibility of the PMO conjugate drug delivery system and make it an attractive and novel topical antimicrobial agent.

Microfluidic droplet platform for ultrahigh-throughput single-cell screening of biodiversity

“…Despite the high pathogenic potential of S. aureus (18), it is rarely associated with dentoalveolar infection (19). We hypothesized that the suppression of S. aureus infection relates to a natural inhibitory activity of some unknown effectors from human oral microbiota.…”

Antibiotics present and future

“…A practical example of the use of our compound involved its curing of Staphylococcus aureus infection of puncture wounds in the backs of mice [4]. One application of the compound a day after infection led to curing of the wounds ten days later.…”

Assessment of configurations and chemistries of bridged nucleic acids-containing oligomers as external guide sequences: a methodology for inhibition of expression of antibiotic resistance genes

“…This result indicates that linking the penetrating peptide to the oligonucleotide analog does not significantly impair the ability of the gapmer to elicit RNase P-mediated degradation of the target mRNA. In the past, phosphorodiamidate morpholino oligonucleotide EGSs conjugated to a permeabilizer peptide efficiently inhibited expression of Gram-negative and Gram-positive genes [69–71]. Conversely, tests to assess LNA/DNAs bound to CPPs were delayed due to difficulties in the chemical conjugation and purification of negatively charged oligomers with the cationic CPPs [67].…”