Title: The Antimicrobial Peptide Gad‐1 Clears Pseudomonas aeruginosa Biofilms under Cystic Fibrosis Conditions
Abstract
Bacterial infections in cystic fibrosis (CF) patients are an emerging health issue and lead to a premature death. CF is a hereditary disease that creates a thick mucus in the lungs that is prone to bacterial biofilm formation, specificallyPseudomonas aeruginosabiofilms. These biofilms are very difficult to treat because many of them have antibiotic resistance that is worsened by the presence of extracellular DNA (eDNA). eDNA helps to stabilize biofilms and can bind antimicrobial compounds to lessen their effects. The metallo‐antimicrobial peptide Gaduscidin‐1 (Gad‐1) eradicates establishedP. aeruginosabiofilms through a combination of modes of action that includes nuclease activity that can cleave eDNA in biofilms. In addition, Gad‐1 exhibits synergistic activity when used with the antibiotics kanamycin and ciprofloxacin, thus making Gad‐1 a new lead compound for the potential treatment of bacterial biofilms in CF patients.
Balmuri, Sricharani Rao; Noaman, Sena; Usman, Huda; Niepa, Tagbo H.(
, Frontiers in Cellular and Infection Microbiology)
Introduction
Chronic lung infection due to bacterial biofilms is one of the leading causes of mortality in cystic fibrosis (CF) patients. Among many species colonizing the lung airways,Pseudomonas aeruginosaandStaphylococcus aureusare two virulent pathogens involved in mechanically robust biofilms that are difficult to eradicate using airway clearance techniques like lung lavage. To remove such biological materials, glycoside hydrolase-based compounds are commonly employed for targeting and breaking down the biofilm matrix, and subsequently increasing cell susceptibility to antibiotics.
Materials and methods
In this study, we evaluate the effects of N-acetyl cysteine (NAC) and Cysteamine (CYST) in disrupting interfacial bacterial films, targeting different components of the extracellular polymeric substances (EPS). We characterize the mechanics and structural integrity of the interfacial bacterial films using pendant drop elastometry and scanning electron microscopy.
Results and discussion
Our results show that the film architectures are compromised by treatment with disrupting agents for 6 h, which reduces film elasticity significantly. These effects are profound in the wild type and mucoidP. aeruginosa, compared toS. aureus. We further assess the effects of competition and cooperation betweenS. aureusandP. aeruginosaon the mechanics of composite interfacial films. Films ofS. aureusand wild-typeP. aeruginosacocultures lose mechanical strength while those ofS. aureusand mucoidP. aeruginosaexhibit improved storage modulus. Treatment with NAC and CYST reduces the elastic property of both composite films, owing to the drugs’ ability to disintegrate their EPS matrix. Overall, our results provide new insights into methods for assessing the efficacy of mucolytic agents against interfacial biofilms relevant to cystic fibrosis infection.
Zaldivar, Gervasio; Feng, Jiachen; Lizarraga, Leonardo; Yu, Yafan; de Campos, Luana; de Oliveira, Kelly Mari Pires; Piepenbrink, Kurt H.; Conda‐Sheridan, Martin; Tagliazucchi, Mario(
, Advanced Materials Interfaces)
Abstract
The colonization of biomedical surfaces by bacterial biofilms is concerning because these microorganisms display higher antimicrobial resistance in biofilms than in liquid cultures. Developing antimicrobial coatings that can be easily applied to medically‐relevant complex‐shaped objects, such as implants and surgical instruments, is an important and challenging research direction. This work reports the preparation of antibacterial surfaces via the electrodeposition of a conformal hydrogel of self‐assembling cationic peptide‐amphiphiles (PAs). Hydrogels of three PAs are electrodeposited: C16K2, C16K3, and C18K2, where Cnis an alkyl chain ofnmethylene groups and Kmis an oligopeptide ofmlysines. The processing variables (electrodeposition time, potential, pH, salt concentration, agitation) enable fine control of film thickness, demonstrating the flexibility of the method and allowing to unravel the mechanisms underlying electrodeposition. The electrochemically prepared hydrogels inhibit the growth ofStaphylococcus aureus,Escherichia coli, andPseudomonas aeruginosain agar plates, and prevent the formation of biofilms ofAcinetobacter baumanniiandP. aeruginosaand the formation ofA. baumanniicolonies in solid media. C16K2and C16K3hydrogels outperform the antimicrobial activity of those of C18K2while maintaining good compatibility with human cells.
Moore, Rebecca E.; Townsend, Steven D.; Gaddy, Jennifer A.(
, ChemBioChem)
Abstract
Streptococcus agalactiaeor Group BStreptococcus(GBS) is a Gram‐positive bacterial pathobiont that is the etiological cause of severe perinatal infections. GBS can colonize the vagina of pregnant patients and invade tissues causing ascending infections of the gravid reproductive tract that lead to adverse outcomes including preterm birth, neonatal sepsis, and maternal or fetal demise. Additionally, transmission of GBS during labor or breastfeeding can also cause invasive infections of neonates and infants. However, human milk has also been shown to have protective effects against infection; a characteristic that is likely derived from antimicrobial and immunomodulatory properties of molecules that comprise human milk. Recent evidence suggests that human milk oligosaccharides (HMOs), short‐chain sugars that comprise 8–20 % of breast milk, have antimicrobial and anti‐biofilm activity against GBS and other bacterial pathogens. Additionally, HMOs have been shown to potentiate the activity of antibiotics against GBS. This review presents the most recent published work that studies the interaction between HMOs and GBS.
ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that causes disease in immunocompromised individuals and individuals with underlying pulmonary disorders. P. aeruginosa virulence is controlled by quorum sensing (QS), a bacterial cell-cell communication mechanism that underpins transitions between individual and group behaviors. In P. aeruginosa , the PqsE enzyme and the QS receptor RhlR directly interact to control the expression of genes involved in virulence. Here, we show that three surface-exposed arginine residues on PqsE comprise the site required for interaction with RhlR. We show that a noninteracting PqsE variant [PqsE(NI)] possesses catalytic activity, but is incapable of promoting virulence phenotypes, indicating that interaction with RhlR, and not catalysis, drives these PqsE-dependent behaviors. Biochemical characterization of the PqsE-RhlR interaction coupled with RNA-seq analyses demonstrates that the PqsE-RhlR complex increases the affinity of RhlR for DNA, enabling enhanced expression of genes encoding key virulence factors. These findings provide the mechanism for PqsE-dependent regulation of RhlR and identify a unique regulatory feature of P. aeruginosa QS and its connection to virulence. IMPORTANCE Bacteria use a cell-cell communication process called quorum sensing (QS) to orchestrate collective behaviors. QS relies on the group-wide detection of molecules called autoinducers (AI). QS is required for virulence in the human pathogen Pseudomonas aeruginosa , which can cause fatal infections in patients with underlying pulmonary disorders. In this study, we determine the molecular basis for the physical interaction between two virulence-driving QS components, PqsE and RhlR. We find that the ability of PqsE to bind RhlR correlates with virulence factor production. Since current antimicrobial therapies exacerbate the growing antibiotic resistance problem because they target bacterial growth, we suggest that the PqsE-RhlR interface discovered here represents a new candidate for targeting with small molecule inhibition. Therapeutics that disrupt the PqsE-RhlR interaction should suppress virulence. Targeting bacterial behaviors such as QS, rather than bacterial growth, represents an attractive alternative for exploration because such therapies could potentially minimize the development of resistance.
@article{osti_10255871,
place = {Country unknown/Code not available},
title = {The Antimicrobial Peptide Gad‐1 Clears Pseudomonas aeruginosa Biofilms under Cystic Fibrosis Conditions},
url = {https://par.nsf.gov/biblio/10255871},
DOI = {10.1002/cbic.202000816},
abstractNote = {Abstract Bacterial infections in cystic fibrosis (CF) patients are an emerging health issue and lead to a premature death. CF is a hereditary disease that creates a thick mucus in the lungs that is prone to bacterial biofilm formation, specificallyPseudomonas aeruginosabiofilms. These biofilms are very difficult to treat because many of them have antibiotic resistance that is worsened by the presence of extracellular DNA (eDNA). eDNA helps to stabilize biofilms and can bind antimicrobial compounds to lessen their effects. The metallo‐antimicrobial peptide Gaduscidin‐1 (Gad‐1) eradicates establishedP. aeruginosabiofilms through a combination of modes of action that includes nuclease activity that can cleave eDNA in biofilms. In addition, Gad‐1 exhibits synergistic activity when used with the antibiotics kanamycin and ciprofloxacin, thus making Gad‐1 a new lead compound for the potential treatment of bacterial biofilms in CF patients.},
journal = {ChemBioChem},
volume = {22},
number = {9},
publisher = {Wiley Blackwell (John Wiley & Sons)},
author = {Portelinha, Jasmin and Angeles‐Boza, Alfredo M.},
}
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