Engineered Cationic Antimicrobial Peptides To Overcome Multidrug Resistance by ESKAPE Pathogens

Deslouches, Berthony; Steckbeck, Jonathan D.; Craigo, Jodi K.; Doi, Yohei; Burns, Jane L.; Montelaro, Ronald C.

doi:10.1128/aac.03937-14

Cited by 112 publications

(130 citation statements)

References 33 publications

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“…It demonstrated high levels of activity against P. aeruginosa and low levels of cytotoxicity against human cells (24)(25)(26). Another AMP chosen for prodrug modification, WR12, comes from a series of salt-resistant peptides synthesized by Deslouches et al (27,28). Its activity and cytotoxicity characteristics are also promising in the CF context, as it was shown to have good activity against a panel of 100 Pseudomonas isolates from CF patients (27,28).…”

mentioning

confidence: 99%

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Forde

Schutte

Reeves

et al. 2016

Antimicrob Agents Chemother

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There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE). However, cytotoxicity remained an issue. Here, we describe the further optimization of the AMP prodrug (pro-AMP) model for CF to produce pro-WMR, a peptide with greatly reduced cytotoxicity (50% inhibitory concentration against CFBE41o-cells, >300 M) compared to that of the previous group of pro-AMPs. The bactericidal activity of pro-WMR was increased in NE-rich bronchoalveolar lavage (BAL) fluid from CF patients (range, 8.4% ؎ 6.9% alone to 91.5% ؎ 5.8% with BAL fluid; P ‫؍‬ 0.0004), an activity differential greater than that of previous pro-AMPs. In a murine model of lung delivery, the pro-AMP modification reduced host toxicity, with pro-WMR being less toxic than the active peptide. Previously, host toxicity issues have hampered the clinical application of AMPs. However, the development of application-specific AMPs with modifications that minimize toxicity similar to those described here can significantly advance their potential use in patients. The combination of this prodrug strategy with a highly active AMP has the potential to produce new therapeutics for the challenging conditions of the CF patient lung.

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confidence: 99%

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Forde

Schutte

Reeves

et al. 2016

Antimicrob Agents Chemother

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“…eCAPs kill rapidly, on the seconds to minutes timescale[12, 13]. The rates of resistance to eCAPs are generally low while the mutants that do arise display variable cross-resistance development rates for natural AMPs[14], which is a topic under intense investigation[15, 16]. To attempt to limit cross-resistance, an intriguing strategy is to utilize eCAPs in conjunction with traditional antibiotics, as the distinct mechanisms of action often result in additive or synergistic activity[11, 17].…”

mentioning

confidence: 99%

“…Due to general membrane disruption activity, eCAPs are often able to kill a broad range of microbial species and strains, even multidrug resistant and select agent pathogens[14, 18, 19]. Considering that infection biofilms are often polymicrobial, treatment with eCAPs is potentially beneficial for their broad-spectrum activity.…”

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confidence: 99%

Clinical potential of engineered cationic antimicrobial peptides against drug resistant biofilms

Melvin

Montelaro

Bomberger

2016

Expert Review of Anti-infective Therapy

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“…Additional approaches may include coupling antimicrobials to nanoparticles, phage therapy, or antimicrobial peptides . Such approaches may also prove useful for other pathogens given their less selective mechanisms …”

Section: Antibiotic Choices For Mrsa Infectionsmentioning

confidence: 99%

Biology and management of methicillin resistantStaphylococcus aureusin cystic fibrosis

Akil

Muhlebach

2018

Pediatric Pulmonology

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Staphylococcus aureus is one of the earliest bacteria isolated from the respiratory tract in people with cystic fibrosis (CF). Its methicillin resistant form, MRSA, has gained attention due to the rapid increase in the last decades and worse outcomes with chronic infection. In the United States, prevalence of MRSA in CF is around 27%, but is much lower (3-18%) in most other countries. Methicillin is typically genetically encoded by the mecA gene, which encodes for an alternative penicillin binding protein (PRBa). This PRBa has low affinity to β-lactams, thereby enabling growth of S. aureus in the presence of penicillinase resistant penicillins and most other β-lactams. Non-mecA positive strains of MRSA, so-called borderline resistant (BORSA) have also been described. In addition to production of toxins, the virulence of S. aureus is conferred by its adaptability allowing persistence in face of antibiotic therapies and host defense. These adaptive growth mechanisms include small colony variants, biofilms, and growth under anaerobic conditions. Several reports have described successful eradication of MRSA, yet only two randomized trials of eradication during early infection have been conducted. A list of MRSA specific antibiotics with dosing relevant to CF patients is presented here. Many of these require special dosing in people with CF. Novel antibiotics are in trials for skin and soft tissue infections and it is unclear if and when those might be available for lung infections. Thus the best strategies for MRSA would be primary prevention.

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Engineered Cationic Antimicrobial Peptides To Overcome Multidrug Resistance by ESKAPE Pathogens

Cited by 112 publications

References 33 publications

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Clinical potential of engineered cationic antimicrobial peptides against drug resistant biofilms

Biology and management of methicillin resistantStaphylococcus aureusin cystic fibrosis

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