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Biochemical and Structural Characterization of the Carbohydrate Transport Substrate-binding-protein SP0092
Published on: October 2, 2017
Harnessing Multiple, Nonproteogenic Substitutions to Optimize CSP:ComD Hydrophobic Interactions in Group 1
Tahmina A Milly1, Emilee R Engler2, Kylie S Chichura2
1Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, NV 89557, USA.
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 in S. 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.
Insights
Researchers optimized Streptococcus pneumoniae quorum-sensing (QS) by modifying the competence-stimulating peptide (CSP1). This work developed potent QS modulators to combat antibiotic resistance and pneumococcal infections.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Discovery
Background:
- Streptococcus pneumoniae causes millions of deaths globally, often due to antibiotic-resistant infections.
- The competence-stimulating peptide (CSP)-mediated quorum-sensing (QS) pathway is crucial for pneumococcal pathogenicity, controlling genetic transformation and the spread of resistance genes.
Purpose of the Study:
- To optimize the interaction between CSP1 and its receptor ComD1.
- To develop novel QS modulators for combating pneumococcal infections and antibiotic resistance.
Main Methods:
- Substitution of proteogenic and nonproteogenic amino acids on the hydrophobic binding face of CSP1.
- Structure-activity relationship analysis to optimize CSP1 potency.
Main Results:
- Generated significant structure-activity data for CSP1 optimization.
- Developed potent QS modulators based on the CSP scaffold.
- Identified potential antimicrobial agents against pneumococcal infections.
Conclusions:
- Modulating the CSP-mediated QS pathway is a viable strategy to reduce pneumococcal infectivity and resistance.
- CSP-based QS modulators represent promising scaffolds for developing new antimicrobial therapies.
