β-Lactam-host defence peptide conjugates as antibiotic prodrug candidates targeting resistant bacteria

Desgranges, Stéphane; Ruddle, Carol C.; Burke, Liam; McFadden, Tara M.; O’Brien, John E.; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Smyth, Timothy P.; Devocelle, Marc

doi:10.1039/c2ra01351g

Cited by 28 publications

(22 citation statements)

References 37 publications

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“…The issue of net charge has been observed previously by our group for cephalothin-Bac8c conjugates, where activity was incompletely masked (50). The use of D-amino acids, which have been shown to be resistant to proteolysis (51)(52)(53), may be necessary to avoid deactivation by the abundant proteases of the CF lung.…”

Section: Figmentioning

confidence: 81%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of Pseudomonas aeruginosa to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of P. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 g/ml). Cytotoxic effects on CFBE41o-cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at in vivo concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

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Section: Figmentioning

confidence: 81%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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“…Cephalothin-Bac8c (15) ( Figure 6) is a conjugate that links cephalothin, a first-generation cephalosporin, with Bac8c-an AMP derived from the bovinedodecapeptidebactenecin [43]-through a carbamate-1,4-triazole linker. Cephalothin-Bac8c is a candidate for β-lactam-AMP prodrug conjugates with promising antibacterial activity targeting resistant extended-spectrum β-lactamase producing Enterobacteriaceae [44].…”

Section: Antimicrobial Peptide Prodrugsmentioning

confidence: 99%

Antibacterial Prodrugs to Overcome Bacterial Resistance

2020

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Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.

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“…Over the past years, many research teams have worked on the pharmacomodulation of AMPs or on developing a number of AMP‐antibiotic combinations or conjugates. These efforts have enhanced ATB efficacy, reduced the toxicity of both components, improved the permeability and broadened the ATB spectrum of conventional antibiotics . With regard to the Trojan horse strategy, we will focus on the conjugation of ATBs with AMPs, the latter serving as delivery vehicules for the former.…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…These efforts have enhanced ATB efficacy, reduced the toxicity of both components, improved the permeability and broadened the ATB spectrum of conventional antibiotics. 105,108,142 With regard to the Trojan horse strategy, we will focus on the conjugation of ATBs with AMPs, the latter serving as delivery vehicules for the former. Other potential applications of AMPs in anti-infectious treatment have already been studied in previous reviews.…”

Section: Introductionmentioning

confidence: 99%

Drug delivery systems designed to overcome antimicrobial resistance

Pham

Loupias

Dassonville‐Klimpt

et al. 2019

Medicinal Research Reviews

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Antimicrobial resistance has emerged as a huge challenge to the effective treatment of infectious diseases. Aside from a modest number of novel anti‐infective agents, very few new classes of antibiotics have been successfully developed for therapeutic use. Despite the research efforts of numerous scientists, the fight against antimicrobial (ATB) resistance has been a longstanding continued effort, as pathogens rapidly adapt and evolve through various strategies, to escape the action of ATBs. Among other mechanisms of resistance to antibiotics, the sophisticated envelopes surrounding microbes especially form a major barrier for almost all anti‐infective agents. In addition, the mammalian cell membrane presents another obstacle to the ATBs that target intracellular pathogens. To negotiate these biological membranes, scientists have developed drug delivery systems to help drugs traverse the cell wall; these are called “Trojan horse” strategies. Within these delivery systems, ATB molecules can be conjugated with one of many different types of carriers. These carriers could include any of the following: siderophores, antimicrobial peptides, cell‐penetrating peptides, antibodies, or even nanoparticles. In recent years, the Trojan horse‐inspired delivery systems have been increasingly reported as efficient strategies to expand the arsenal of therapeutic solutions and/or reinforce the effectiveness of conventional ATBs against drug‐resistant microbes, while also minimizing the side effects of these drugs. In this paper, we aim to review and report on the recent progress made in these newly prevalent ATB delivery strategies, within the current context of increasing ATB resistance.

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β-Lactam-host defence peptide conjugates as antibiotic prodrug candidates targeting resistant bacteria

Cited by 28 publications

References 37 publications

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Antibacterial Prodrugs to Overcome Bacterial Resistance

Drug delivery systems designed to overcome antimicrobial resistance

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