An official website of the United States government
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. pneumoniaecan 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.
more »
« less
Optimizing CSP1 analogs for modulating quorum sensing in Streptococcus pneumoniae with bulky, hydrophobic nonproteogenic amino acid substitutions
The prompt appearance of multiantibiotic-resistant bacteria necessitates finding alternative treatments that can attenuate bacterial infections while minimizing the rate of antibiotic resistance development. Streptococcus pneumoniae , a notorious human pathogen, is responsible for severe antibiotic-resistant infections. Its pathogenicity is influenced by a cell-density communication system, termed quorum sensing (QS). As a result, controlling QS through the development of peptide-based QS modulators may serve to attenuate pneumococcal infections. Herein, we set out to evaluate the impact of the introduction of bulkier, nonproteogenic side-chain residues on the hydrophobic binding face of CSP1 to optimize receptor-binding interactions in both of the S. pneumoniae specificity groups. Our results indicate that these substitutions optimize the peptide–protein binding interactions, yielding several pneumococcal QS modulators with high potency. Moreover, pharmacological evaluation of lead analogs revealed that the incorporation of nonproteogenic amino acids increased the peptides’ half-life towards enzymatic degradation while remaining nontoxic. Overall, our data convey key considerations for SAR using nonproteogenic amino acids, which provide analogs with better pharmacological properties.
more »
« less
- Award ID(s):
- 1808370
- 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
-
-
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) inStaphylococcus 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 vivoand could advance the development of new strategies for skin infection control.more » « less
-
Proteins and peptides in nature are almost exclusively made from l -amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d -amino acids in biological processes have been revealed. Over 30 d -amino acid containing peptides (DAACPs) have been discovered in animals where at least one l -residue has been isomerized to the d -form via an enzyme-catalyzed process. In Aplysia californica , GdFFD and GdYFD (the lower-case letter “d” indicates a d -amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d -residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand–receptor interactions in the absence of high-resolution structural data.more » « less
-
Abstract Pseudomonas aeruginosais an increasingly antibiotic-resistant pathogen that causes severe lung infections, burn wound infections, and diabetic foot infections.P. aeruginosaproduces the siderophore pyochelin through the use of a non-ribosomal peptide synthetase (NRPS) biosynthetic pathway. Targeting members of siderophore NRPS proteins is one avenue currently under investigation for the development of new antibiotics against antibiotic-resistant organisms. Here, the crystal structure of the pyochelin adenylation domain PchD is reported. The structure was solved to 2.11 Å when co-crystallized with the adenylation inhibitor 5′-O-(N-salicylsulfamoyl)adenosine (salicyl-AMS) and to 1.69 Å with a modified version of salicyl-AMS designed to target an active site cysteine (4-cyano-salicyl-AMS). In the structures, PchD adopts the adenylation conformation, similar to that reported for AB3403 fromAcinetobacter baumannii. Graphical abstractmore » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1CB00224D
