Polyproline peptide targets Klebsiella pneumoniae polysaccharides to collapse biofilms

De los Santos, Laura; Beckman, Robert L.; DeBarro, Christina; Keener, James E.; Torres, Marcelo D.T.; Fuente-Nunez, Cesar de la; Brodbelt, Jennifer S.; Fleeman, Renee M.

doi:10.1016/j.xcrp.2024.101869

Cited by 2 publications

(3 citation statements)

References 77 publications

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“…Interestingly, contrary to what was described above, the ability to bind DNA and the lack of effect on the membranes of S. aureus and E. coli revealed that PAMP may also have an intracellular mechanism of action (Ajish et al, 2020). This behavior has been demonstrated for other AMPs such as bac7, whose mechanism of action can vary depending on the bacterial species (De los Santos et al, 2024).…”

Section: Introductionmentioning

confidence: 72%

In silico optimization of analogs derived pro‐adrenomedullin peptide to evaluate antimicrobial potential

Quigua‐Orozco,

Andrade,

Oshiro

et al. 2024

Chem Biol Drug Des

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Diverse computational approaches have been widely used to assist in designing antimicrobial peptides with enhanced activities. This tactic has also been used to address the need for new treatment alternatives to combat resistant bacterial infections. Herein, we have designed eight variants from a natural peptide, pro‐adrenomedullin N‐terminal 20 peptide (PAMP), using an in silico pattern insertion approach, the Joker algorithm. All the variants show an α‐helical conformation, but with differences in the helix percentages according to circular dichroism (CD) results. We found that the C‐terminal portion of PAMP may be relevant for its antimicrobial activities, as revealed by the molecular dynamics, CD, and antibacterial results. The analogs showed variable antibacterial potential, but most were not cytotoxic. Nevertheless, PAMP2 exhibited the most potent activities against human and animal‐isolated bacteria, showing cytotoxicity only at a substantially higher concentration than its minimal inhibitory concentration (MIC). Our results suggest that the enhanced activity in the profile of PAMP2 may be related to their particular physicochemical properties, along with the adoption of an amphipathic α‐helical arrangement with the conserved C‐terminus portion. Finally, the peptides designed in this study can constitute scaffolds for the design of improved sequences.

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Section: Introductionmentioning

confidence: 72%

In silico optimization of analogs derived pro‐adrenomedullin peptide to evaluate antimicrobial potential

Quigua‐Orozco,

Andrade,

Oshiro

et al. 2024

Chem Biol Drug Des

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“…To investigate the correlation between mucoviscosity and bio lm formation in this diverse set of K. pneumoniae isolates, we assessed the percent mucoviscosity to compare to our bio lm density analysis. This assessment was done as previously described using slow centrifugation and calculating the percent mucoviscosity as the change in supernatant optical density at 600 nm 14,19,33 .…”

Section: Tablementioning

confidence: 99%

“…Surface attachment and bio lm formation are a crucial rst step of the infection process, but this important virulence trait is di cult to link to a genotype, or predict from genomic data, [15][16][17] . Characterization of the matrix of K. pneumoniae bio lms found it is largely composed of lipopolysaccharides and capsular polysaccharides 18,19 . Previous studies have highlighted the importance of capsular polysaccharides in bio lm formation and implicated its deleterious effect through occluding the mbriae that allow for surface attachment 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Diverse polysaccharide production and biofilm formation abilities of clinical Klebsiella pneumoniae

IV,

Cella,

Azarian

et al. 2024

Preprint

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Klebsiella pneumoniae infections have become a growing threat for human health. The lack of understanding of the relationship between antibiotic resistance, mucoviscosity, and biofilm formation in clinical isolates impedes our abilities to effectively predict K. pneumoniae infection outcomes. These traits are also associated with fitness in natural populations and more specifically within a host. The Multidrug-Resistant Organism Repository and Surveillance Network offers a unique opportunity into the genetic and phenotypic variabilities in the K. pneumoniae isolates encountered in the clinics today. To this end, we compared the genetic profiles of these isolates with the phenotypic biofilm formation abilities, percent mucoviscosity, and growth rates. We found most isolates formed limited biofilm, although a select group of isolates could form extremely robust biofilms. Variation in biofilm formation could not be explained by difference in growth rate, suggesting specific genetic and physical determinants. Interestingly, the most mucoid strains in the populations were lacking the genetic element regulating the mucoid phenotype and three of these isolates were able to form robust biofilms. There was a significant phenotype-genotype correlation with decreased biofilm formation and an insertion sequence in the transcriptional activator of the type III fimbrial system. Finally, confocal microscopy highlighted the structural and spatial heterogeneity of biofilm among the most robust biofilm formers not detected by traditional methods. The combination of phenotypic, genomic and image analyses allowed us to reveal an unexpected phenotypic diversity and an intricate relation between growth, mucoviscosity and specific virulence-associated genetic determinants.

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Polyproline peptide targets Klebsiella pneumoniae polysaccharides to collapse biofilms

Cited by 2 publications

References 77 publications

In silico optimization of analogs derived pro‐adrenomedullin peptide to evaluate antimicrobial potential

In silico optimization of analogs derived pro‐adrenomedullin peptide to evaluate antimicrobial potential

Diverse polysaccharide production and biofilm formation abilities of clinical Klebsiella pneumoniae

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