Objective: Chronic suppurative otitis media (CSOM) is characterized by a chronically draining middle ear. CSOM is typically treated with multiple courses of antibiotics or antiseptics which are successful in achieving quiescence; however, the disease is prone to relapse. Understanding why these treatment failures occur is essential. Study Design: The minimum inhibitory concentration (MIC), minimal biofilm eradication concentration, and the inhibitory zone were determined for ototopicals and ofloxacin for the laboratory strains and CSOM-derived isolates. The percentage of persister cells and bacterial biofilm formation were measured. Disease eradication was tested in a validated invivo model of CSOM after treatment with ofloxacin. Setting: Microbiology Laboratory. Methods: Basic science experiments were performed to measure the effectiveness of a number of compounds against CSOM bacteria in a number of distinct settings. Results: The minimal biofilm eradication concentration is higher than is physiologically achievable with commercial preparations, except for povo-iodine. Clincial isolates of CSOM have equivalent biofilm-forming ability but increased proportions of persister cells. Ofloxacin can convert to inactive disease temporarily but fails to eradicate disease in an in-vivo model. Conclusions: Higher percentages of persister cells in clinical CSOM isolates are associated with resistance to ototopicals. Current ototopicals, except povo-iodine, have limited clinical effectiveness; however, it is unknown what the maximum achievable concentration is and there are ototoxicity concerns. Fluoroquinolones, while successful in producing inactive disease in the short term, have the potential to encourage antimicrobial resistance and disease recalcitrance and do not achieve a permanent remission. Given these limitations, clinicians should consider surgery earlier or use of clinically safe concentrations of povo-iodine earlier into the treatment algorithm.
Although persister cells are the root cause of resistance development and relapse of chronic infections, more attention has been focused on developing antimicrobial agents against resistant bacterial strains than on developing anti-persister agents. Frustratingly, the global preclinical antibacterial pipeline does not include any anti-persister drug. Therefore, the central point of this work is to explore antimicrobial peptidomimetics called peptoids (sequence-specific oligo- N -substituted glycines) as a new class of anti-persister drugs. In this study, we demonstrate that one particular antimicrobial peptoid, the sequence-specific pentamer TM5, is active against planktonic persister cells and sterilizes biofilms formed by both Gram-negative and Gram-positive bacteria. Moreover, we demonstrate the potential of TM5 to inhibit cytokine production induced by lipopolysaccharides from Gram-negative bacteria. We anticipate that this work can pave the way to the development of new anti-persister agents based on antimicrobial peptoids of this class to simultaneously help address the crisis of bacterial resistance and reduce the occurrence of the relapse of chronic infections.
Background Chronic suppurative otitis media (CSOM) is the most common cause of permanent hearing loss in children in the developing world. A large component of the permanent hearing loss is sensory in nature and our understanding of the mechanism of this has so far been limited to post-mortem human specimens or acute infection models that are not representative of human CSOM. In this report, we assess cochlear injury in a validated Pseudomonas aeruginosa (PA) CSOM mouse model. Methods We generated persisters (PCs) and inoculated them into the mouse middle ear cavity. We tracked infection with IVIS and detected PA using RT-PCR. We assessed cochlear damage and innate immunity by Immunohistochemistry. Finally, we evaluated cytokines with multiplex assay and quantitative real-time PCR. Results We observed outer hair cell (OHC) loss predominantly in the basal turn of the cochlear at 14 days after bacterial inoculation. Macrophages, not neutrophils are the major immune cells in the cochlea in CSOM displaying increased numbers and a distribution correlated with the observed cochlear injury. The progression of the morphological changes suggests a transition from monocytes into tissue macrophages following infection. We also show that PA do not enter the cochlea and live bacteria are required for cochlear injury. We characterized cytokine activity in the CSOM cochlea. Conclusions Taken together, this data shows a critical role for macrophages in CSOM-mediated sensorineural hearing loss (SNHL).
Escherichia coli biofilms are a major causative agent of many intestinal infections, and there is ongoing research aimed at E. coli biofilm eradication. Gold nanoclusters (AuNCs) conjugated with various surface ligands have been extensively investigated for antimicrobial properties and provide a potential solution. There is little known about their in vivo safety because current standards of nanosafety research involve incubation of AuNCs with cells in vitro to confirm biocompatibility. In addition to systemic administration, nanosafety research on AuNC-based antimicrobials designed to treat gastrointestinal infections must also consider the potential for inducing gastrointestinal disorders. We report the design and application of two AuNCs coated with either hydroxyl (AuNC@PEG-OH)- or amine (AuNC@PEG-NH2)-functionalized poly(ethylene glycol), which enables the eradication of E. coli biofilms. Gastrointestinal safety of AuNC@PEG-OH and AuNC@PEG-NH2 was evaluated in healthy mice up to 35 days after administration by oral gavage at a dose of 10 mg/kg (or 1 mg/mL) daily for 14 days. No changes were detected in the histopathology of major organs, serum chemistry, hematology, and feces. Thus, oral administration of AuNCs is unlikely to be of concern for systemic toxicity or in the induction of gastrointestinal illnesses. Further studies on increasing time exposure and doses are necessary to determine whether toxicity occurs at higher doses or whether there is no adverse effect limit.
Anionic AuNC@CPP enters the cells and dissipates the proton gradient (ΔpH), which is compensated by an increase in electrical potential (ΔΨ) that leads to membrane hyperpolarization and enhances the susceptibility of persisters to antibiotics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.