A Rationally Designed Antimicrobial Peptide from Structural and Functional Insight of Clostridium difficile Translation Initiation Factor 1
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Abstract
A significant increase of hospital-acquired bacterial infections during the COVID-19 pandemic has become an urgent medical problem. Clostridioides difficile is an urgent antibiotic-resistant bacterial pathogen and a leading causative agent of nosocomial infections. The increasing recurrence of C. difficile infection and antibiotic resistance in C. difficile has led to an unmet need for discovery of new compounds distinctly different from present antimicrobials, while antimicrobial peptides as promising alternatives to conventional antibiotics have attracted growing interest recently. Protein synthesis is an essential metabolic process in all bacteria and a validated antibiotic target. Initiation factor 1 from C. difficile (Cd-IF1) is the smallest of the three initiation factors that acts to establish the 30S initiation complex to initiate translation during protein biosynthesis. Here we report the solution NMR structure of Cd-IF1 which adopts a typical β-barrel fold and consists of a five-stranded β-sheet and one short α-helix arranged in the sequential order β1-β2-β3-α1-β4-β5. The interaction of Cd-IF1 with the 30S ribosomal subunit was studied by NMR titration for the construction of a structural model of Cd-IF1 binding with the 30S subunit. The short α-helix in IF1 was found to be critical for IF1 ribosomal binding. A peptide derived from this α-helix was tested and displayed a high ability to inhibit the growth of C. difficile and other bacterial strains. These results provide a clue for rational design of new antimicrobials.
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I have two questions around this!
- I'm assuming that the % identity for this gene is fairly reflective of phylogenetic distances between these species as a whole (given that IF1 is related to an essential process). Is this true?
- I'm curious if you know how you would design the peptide differently if your target species was another one of these, such as Burkholderia. (Big picture, wondering how much room there is for rationally designing specificity to avoid off-target effects with other bacterial species).
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Intriguingly, the MIC values for the Gram-positive strains were about 10 times lower than that of the Gram-negative bacteria (Table II), suggesting the peptide is more effective in inhibiting Gram-positive than Gram-negative bacteria.
This interesting. I was curious whether you think that there could be some indirect reasons for this difference that are distinct from IF1 structure? For example, perhaps some of this difference could be due to differences in cell envelope between Gram-positive and -negative, which could impact 1) delivery of peptide across the envelope, or 2) toxic AMP-like effects via physical interactions with the envelope (as you mention later). Would love to hear more of your thoughts on this. Thanks.
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