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Synthetic mucus biomaterials synergize with antibiofilm agents to combat Pseudomonas aeruginosa biofilms.

ABSTRACT: Bacterial biofilms are often highly resistant to antimicrobials causing persistent infections which when not effectively managed can significantly worsen clinical outcomes. As such, alternatives to standard antibiotic therapies have been highly sought after to address difficult-to-treat biofilm-associated infections. We hypothesized a biomaterial-based approach using the innate functions of mucins to modulate bacterial surface attachment and virulence could provide a new therapeutic strategy against biofilms. Based on our testing in Pseudomonas aeruginosa biofilms, we found synthetic mucus biomaterials can inhibit biofilm formation and significantly reduce the thickness of mature biofilms. In addition, we evaluated if synthetic mucus biomaterials could work synergistically with DNase and/or α-amylase for enhanced biofilm dispersal. Combination treatment with these antibiofilm agents and synthetic mucus biomaterials resulted in up to 3 log reductions in viability of mature P. aeruginosa biofilms. Overall, this work provides a new bio-inspired, combinatorial approach to address biofilms and antibiotic-resistant bacterial infections.

SUBMITTER: Yang S

PROVIDER: S-EPMC11326292 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Synthetic mucus biomaterials synergize with antibiofilm agents to combat <i>Pseudomonas aeruginosa</i> biofilms.

Yang Sydney S Stern Alexa A Duncan Gregg G

bioRxiv : the preprint server for biology 20240810

Bacterial biofilms are often highly resistant to antimicrobials causing persistent infections which when not effectively managed can significantly worsen clinical outcomes. As such, alternatives to standard antibiotic therapies have been highly sought after to address difficult-to-treat biofilm-associated infections. We hypothesized a biomaterial-based approach using the innate functions of mucins to modulate bacterial surface attachment and virulence could provide a new therapeutic strategy aga ...[more]

PMID: 39149383

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Project description:Pseudomonas aeruginosa is a notorious opportunistic pathogen associated with chronic biofilm-related infections, posing a significant challenge to effective treatment strategies. Quorum sensing (QS) and biofilm formation are critical virulence factors employed by P. aeruginosa, contributing to its pathogenicity and antibiotic resistance. Other than the homoserine-based QS systems, P. aeruginosa also possesses the quinolone-based Pseudomonas quinolone signal (PQS) QS signaling. Synthesis of the PQS signaling molecule is achieved by the pqsABCDEH operon, whereas the PQS signaling response was mediated by the PqsR receptor. In this study, we report the discovery of a novel natural compound, Juglone, with potent inhibitory effects on pqs QS and biofilm formation in P. aeruginosa. Through an extensive screening of natural compounds from diverse sources, we identified Juglone, a natural compound from walnut, as a promising candidate. We showed that Juglone could inhibit PqsR and the molecular docking results revealed that Juglone could potentially bind to the PqsR active site. Furthermore, Juglone could inhibit pqs-regulated virulence factors, such as pyocyanin and the PQS QS signaling molecule. Juglone could also significantly reduce both the quantity and quality of P. aeruginosa biofilms. Notably, this compound exhibited minimal cytotoxicity toward mammalian cells, suggesting its potential safety for therapeutic applications. To explore the clinical relevance of Juglone, we investigated its combinatorial effects with colistin, a commonly used antibiotic against P. aeruginosa infections. The Juglone-colistin combinatorial treatment could eliminate biofilms formed by wild-type P. aeruginosa PAO1 and its clinical isolates collected from cystic fibrosis patients. The Juglone-colistin combinatorial therapy dramatically improved colistin efficacy and reduced inflammation in a wound infection model, indicating its potential for clinical utility. In conclusion, the discovery of Juglone provides insights into the development of innovative antivirulence therapeutic strategies to combat P. aeruginosa biofilm-associated infections.

Project description:BackgroundIncreased prevalence of antimicrobial resistance coupled with a lack of new antibiotics against Gram-negative bacteria emphasize the imperative for novel therapeutic strategies. Colistin-resistant Pseudomonas aeruginosa constitutes a challenge, where conventional treatment options lack efficacy, in particular for biofilm-associated infections. Previously, synergy of colistin with other antibiotics was explored as an avenue for the treatment of colistin-resistant infections, and recently we reported our efforts towards colistin analogs capable of combating planktonic colistin-resistant strains.AimsThe aim of the present study was to investigate whether analogs of polymyxin B with improved potency in wild-type and moderate resistant Gram-negative pathogens would retain similarly increased activity in highly colistin-resistant clinical P. aeruginosa isolates (in planktonic and biofilm growth) when applied alone and in combination with rifampicin.Materials and methodsIn this in vitro study, we tested three analogs of polymyxin B prepared by solid-phase peptide synthesis. Antimicrobial susceptibility testing was performed by measurement of minimum inhibitory concentrations via the broth microdilution method. Interactions between two antimicrobials was quantified in a checkerboard broth microdilution assay by calculating the fractional inhibitory concentration index for each combination. For testing of antibiofilm activity a previously described model with alginate beads encapsulating a biofilm culture was applied. The minimum biofilm eradication concentrations (MBECs) were evaluated, and the fractional biofilm eradication concentration indices were calculated. Three recently identified colistin analogs (CEP932, CEP936 and CEP938) were tested against three isogenic pairs of colistin-susceptible and colistin-resistant P. aeruginosa clinical isolates as well as the reference strain PAO1.ResultsFor bacteria in planktonic growth CEP938 retained almost full potency in all three resistant isolates, while exhibiting similar activity as colistin in susceptible isolates. Against biofilms CEP938 was slightly more potent against PAO1 as compared to colistin, while also retaining activity against a biofilm of the colistin-resistant strain 41,782/98. Next, synergy between CEP938 and the antibiotic rifampicin was explored. Interestingly, CEP938 did not exhibit synergy with rifampicin in planktonic cultures. Importantly, for colistin-resistant biofilms the CEP938-rifampicin combination demonstrated activity superior to that found for the colistin-rifampicin combination.ConclusionsThe present study showed in vitro efficacy of CEP938 against both colistin-susceptible and colistin-resistant P. aeruginosa biofilms as well as an ability of CEP938 to synergize with rifampicin in biofilm eradication.

Project description:Bacterial biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa pose significant challenges in treating cystic fibrosis (CF) airway infections due to their resistance to antibiotics. New therapeutic approaches are urgently needed to treat these chronic infections. This study aimed to investigate the antibiofilm potential of various plant extracts, specifically targeting mucoid and small colony variants of P. aeruginosa and S. aureus and strains. Moreover, it aimed to gain insights into the mechanisms of action and the potential phytochemicals responsible for antibiofilm activity. Solid-liquid extractions were performed on seven biomasses using water and ethanol (70 and 96 %) under controlled conditions, resulting in 21 distinct plant extracts. These extracts were evaluated for extraction yield, antioxidant activity, phenolic content, chemical composition by HPLC-TOF-MS, and antibiofilm activity using a 96-well plate assay, followed by crystal violet staining, bacterial adhesion assessment, and brightfield microscopy. Our findings revealed that aqueous extracts exhibited the highest inhibition of biofilm formation, with cinnamon bark and moringa seeds showing strong antibiofilm activity against both bacterial species. Brightfield microscopy confirmed that these extracts effectively inhibited biofilm formation. Chemical analysis identified key bioactive compounds, including moringin, benzaldehyde, coumarin, and quinic acid, which likely contribute to the observed antibiofilm effects. Recognizing that the antibiofilm properties of moringin, a common compound in both moringa seed and cinnamon bark extracts, remain underexplored, we conducted potential target identification via PharmMapper and molecular docking analyses to provide a foundation for future research. Computational analyses indicated that moringin might inhibit aspartate-semialdehyde dehydrogenase in P. aeruginosa and potentially interact with an unknown target in S. aureus. In conclusion, moringa seed and cinnamon bark extracts demonstrated significant potential for developing new therapies targeting biofilm-associated infections in CF. Further studies are needed to validate the computational predictions, identify the bacterial targets, and elucidate the precise mechanisms behind moringin's antibiofilm activity, which is likely the potential key contributor to the observed activity of the moringa and cinnamon bark extracts.

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Synthetic mucus biomaterials synergize with antibiofilm agents to combat Pseudomonas aeruginosa biofilms.

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Synthetic mucus biomaterials synergize with antibiofilm agents to combat <i>Pseudomonas aeruginosa</i> biofilms.

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