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Biofilm Heterogeneity-Adaptive Photoredox Catalysis Enables Red Light-Triggered Nitric Oxide Release for Combating Drug-Resistant Infections

ABSTRACT: The formation of biofilms is closely associated with persistent and chronic infections, and physiological heterogeneity such as pH and oxygen gradients renders biofilms highly resistant to conventional antibiotics. To date, effectively treating biofilm infections remains a significant challenge. Herein, we report the fabrication of micellar nanoparticles adapted to heterogeneous biofilm microenvironments, enabling nitric oxide (NO) release through two distinct photoredox catalysis mechanisms. The key design feature involves the use of tertiary amine (TA) moieties, which function as sacrificial agents to avoid the quenching of photocatalysts under normoxic and neutral pH conditions and proton acceptors at acidic pH to allow deep biofilm penetration. This biofilm-adaptive NO-releasing platform shows excellent antibiofilm activity against ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilms both in vitro and in a mouse skin infection model, providing a strategy for combating biofilm heterogeneity and biofilm-related infections.

ORGANISM(S): Bacteria

PROVIDER: GSE246965 | GEO | 2023/11/22

REPOSITORIES: GEO

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Project description:P. aeruginosa is the leading cause of death in patients with cystic fibrosis patients and one of the most problematic bacterial pathogens responsible for hospital-acquired infections. This pathogen has a high capacity to form biofilms on inert and living surfaces. This lifestyle allows it to persist in various hospital niches or on medical device which become vectors of contamination. Chronic infections are extremely complicated to eradicate due to the remarkable antimicrobial resistance of biofilms leading to a persistence in the tissue and an immune system exhaustion. It is therefore becoming essential to understand the mechanisms of biofilm formation to find new therapeutic targets in order to develop effective antibiofilm strategies. We previously identified in P. aeruginosa PA01 biofilms an accumulation of a hypothetical protein named PA3731 and its deletion impacted the biofilm formation. Similarly, to PspA, a protein from the well-known Psp system of E. coli, PA3731 is a has a predicted structure mostly helical, a PspA/IM30 domain and was accumulated during an osmotic shock. In P. aeruginosa genome, PA3731 appears to form a cluster with 3 genes (PA3732 to PA3729) that we named BAC system for “Biofilm Associated Cluster”. Here we worked on the PA14 strain and focus our study on PA14_16140, the PA3732 homologue. Using a ∆16140 mutant and phenotypic approach, we confirmed the role of the BAC system in the virulence and biofilm formation. We added supplementary genes coding the BAC system and demonstrate that altogether they form an operonic structure regulates by RpoN. We get further insight the role PA14_16140 by proteomic quantitative approach revealing an accumulation of the BAC system proteins in ∆16140 biofilms suggesting its regulatory role of the bac operon. Moreover, we present here the first crystallographic structure of PA14_16140. To summarise, according to our studies, and although further analysis is still required, this newly discovered operon appears composed firstly of its regulator and then of a homologous PspA.

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Biofilm Heterogeneity-Adaptive Photoredox Catalysis Enables Red Light-Triggered Nitric Oxide Release for Combating Drug-Resistant Infections

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