- Award ID(s):
- 1808370
- NSF-PAR ID:
- 10320956
- Date Published:
- Journal Name:
- RSC Chemical Biology
- Volume:
- 3
- Issue:
- 3
- ISSN:
- 2633-0679
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract Streptococcus pneumoniae (pneumococcus) is a human pathobiont that causes drastic antibiotic‐resistant infections and is responsible for millions of deaths universally. Pneumococcus pathogenicity relies on the competence‐stimulating peptide (CSP)‐mediated quorum‐sensing (QS) pathway that controls competence development for genetic transformation and, consequently, the spread of antibiotic resistance and virulence genes. Modulation of QS inS. pneumoniae can therefore be used to enervate pneumococcal infectivity as well as minimize the susceptibility to resistance development. In this work, we sought to optimize the interaction of CSP1 with its cognate transmembrane histidine kinase receptor (ComD1) through substitution of proteogenic and nonproteogenic amino acids on the hydrophobic binding face of CSP1. The findings from this study not only provided additional structure–activity data that are significant in optimizing CSP1 potency, but also led to the development of potent QS modulators. These CSP‐based QS modulators could be used as privileged scaffolds for the development of antimicrobial agents against pneumococcal infections. -
The threat of antibiotic resistance warrants the discovery of agents with novel antimicrobial mechanisms. Antimicrobial peptides (AMPs) directly disrupting bacterial membranes may overcome resistance to traditional antibiotics. AMP development for clinical use has been mostly limited to topical application to date. We developed a rational framework for systematically addressing this challenge using libraries composed of 86 novel Trp- and Arg-rich engineered peptides tested against clinical strains of the most common multidrug-resistant bacteria known as ESKAPE pathogens. Structure-function correlations revealed minimum lengths (as low as 16 residues) and Trp positioning for maximum antibacterial potency with mean minimum inhibitory concentration (MIC) of 2–4 μM and corresponding negligible toxicity to mammalian cells. Twelve peptides were selected based on broad-spectrum activity against both gram-negative and -positive bacteria and <25% toxicity to mammalian cells at maximum test concentrations. Most of the selected PAX remained active against the colistin-resistant clinical strains. Of the selected peptides, the shortest (the 16-residue E35) was further investigated for antibacterial mechanism and proof-of-concept in vivo efficacy. E35 killed an extensively-resistant isolate of Pseudomonas aeruginosa (PA239 from the CDC, also resistant to colistin) by irreversibly disrupting the cell membranes as shown by propidium iodide incorporation, using flow cytometry and live cell imaging. As proof of concept, in vivo toxicity studies showed that mice tolerated a systemic dose of up to 30 mg/kg peptide and were protected with a single 5 mg/kg intravenous (IV) dose against an otherwise lethal intraperitoneal injection of PA239. Efficacy was also demonstrated in an immune-compromised Klebsiella pneumoniae infection model using a daily dose of 4mg/kg E35 systemically for 2 days. This framework defines the determinants of efficacy of helical AMPs composed of only cationic and hydrophobic amino acids and provides a path for a potential departure from the restriction to topical use of AMPs toward systemic application.more » « less
-
more » « less
Abstract Bacteria utilize a cell density‐dependent communication system called quorum sensing (QS) to coordinate group behaviors. In Gram‐positive bacteria, QS involves the production of and response to auto‐inducing peptide (AIP) signaling molecules to modulate group phenotypes, including pathogenicity. As such, this bacterial communication system has been identified as a potential therapeutic target against bacterial infections. More specifically, developing synthetic modulators derived from the native peptide signal paves a new way to selectively block the pathogenic behaviors associated with this signaling system. Moreover, rational design and development of potent synthetic peptide modulators allows in depth understanding of the molecular mechanisms that drive QS circuits in diverse bacterial species. Overall, studies aimed at understanding the role of QS in microbial social behavior could result in the accumulation of significant knowledge of microbial interactions, and consequently lead to the development of alternative therapeutic agents to treat bacterial infectivity. In this review, we discuss recent advances in the development of peptide‐based modulators to target QS systems in Gram‐positive pathogens, with a focus on evaluating the therapeutic potential associated with these bacterial signaling pathways.
-
more » « less
Abstract There is significant interest in approaches to the treatment of bacterial infections that block virulence without creating selective pressures that lead to resistance. Here, we report the development of an “anti‐virulence” strategy that exploits the activity of potent synthetic inhibitors of quorum sensing (QS) in
Staphylococcus aureus . We identify peptide‐based inhibitors of QS that are resistant to sequestration or degradation by components of murine tissue and demonstrate that encapsulation of a lead inhibitor in degradable polymer microparticles provides materials that substantially inhibit QSin vitro . Using a murine abscess model, we show that this inhibitor attenuates methicillin‐resistantS. aureus (MRSA) skin infectionsin vivo , and that sustained release of the inhibitor from microparticles significantly improved outcomes compared to mice that received a single‐dose bolus. Our results present an effective and modular approach to controlling bacterial virulencein vivo and could advance the development of new strategies for skin infection control. -
more » « less
Abstract There is significant interest in approaches to the treatment of bacterial infections that block virulence without creating selective pressures that lead to resistance. Here, we report the development of an “anti‐virulence” strategy that exploits the activity of potent synthetic inhibitors of quorum sensing (QS) in
Staphylococcus aureus . We identify peptide‐based inhibitors of QS that are resistant to sequestration or degradation by components of murine tissue and demonstrate that encapsulation of a lead inhibitor in degradable polymer microparticles provides materials that substantially inhibit QSin vitro . Using a murine abscess model, we show that this inhibitor attenuates methicillin‐resistantS. aureus (MRSA) skin infectionsin vivo , and that sustained release of the inhibitor from microparticles significantly improved outcomes compared to mice that received a single‐dose bolus. Our results present an effective and modular approach to controlling bacterial virulencein vivo and could advance the development of new strategies for skin infection control.
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1CB00224D
