ABSTRACT
BACKGROUND: Nontuberculous mycobacteria (NTM), an extremely rare pathogen causing cervicofacial infections, may result in permanent hearing impairment or intracranial complications. Due to the lack of specific manifestations during the initial onset of NTM otomastoiditis, physicians may misdiagnose it as cholesteatoma or other common bacterial infections. PATIENT CONCERNS: A 44-year-old male who complained of left-sided aural fullness, otalgia, and dizziness for 2 months. DIAGNOSIS: The initial diagnosis was hypothesized to be cholesteatoma based on a whitish mass with mucoid discharge filling the entire outer ear canal on otoscopy and left-sided mixed hearing loss. However, NTM was identified by microbial culture at the 2-month follow-up after surgery. INTERVENTIONS: The patient underwent a left-sided exploratory tympanotomy. Because NTM otomastoiditis was diagnosed, 3 weeks of starting therapies were administered with azithromycin (500 mg/day, oral administration), cefoxitin (3 g/day, intravenous drip), and amikacin (750 mg/day, intravenous drip). The maintenance therapies were azithromycin (500 mg/day, oral administration) and doxycycline (200 mg/day, oral administration) for 7 months. OUTCOMES: The patient's clinical condition improved initially after surgery, but the otomastoiditis gradually worsened, combined with subtle meningitis, 2 months after surgery. The external auditory canal became swollen and obstructed, making it difficult to monitor the treatment efficacy through otoscopy. Thus, we used regular vestibular function tests, including static posturography, cervical vestibular evoked myogenic potentials, and video Head Impulse Test, to assess recovery outcomes. After antibiotic treatment, the infectious symptoms subsided significantly, and there was no evidence of infection recurrence 7 months after treatment. Improvements in static posturography and cervical vestibular evoked myogenic potentials were compatible with the clinical manifestations, but video Head Impulse Test showed an unremarkable correlation. LESSONS: The clinical condition of NTM otomastoiditis may be evaluated using vestibular tests if patients have symptoms of dizziness.
Subject(s)
Cholesteatoma , Vestibular Evoked Myogenic Potentials , Male , Humans , Adult , Dizziness/diagnosis , Nontuberculous Mycobacteria , Azithromycin , Vestibular Function Tests , Vertigo/diagnosis , Vestibular Evoked Myogenic Potentials/physiologyABSTRACT
A strategy was described to design antimicrobial peptides (AMPs) with enhanced salt resistance and antiendotoxin activities by linking two helical AMPs with the Ala-Gly-Pro (AGP) hinge. Among the designed peptides, KR12AGPWR6 demonstrated the best antimicrobial activities even in high salt conditions (NaCl ~300 mM) and possessed the strongest antiendotoxin activities. These activities may be related to hydrophobicity, membrane-permeability, and α-helical content of the peptide. Amino acids of the C-terminal helices were found to affect the peptide-induced permeabilization of LUVs, the α-helicity of the designed peptides under various LUVs, and the LPS aggregation and size alternation. A possible model was proposed to explain the mechanism of LPS neutralization by the designed peptides. These findings could provide a new approach for designing AMPs with enhanced salt resistance and antiendotoxin activities for potential therapeutic applications.
Subject(s)
Endotoxemia/drug therapy , Lipopolysaccharides/antagonists & inhibitors , Pore Forming Cytotoxic Proteins/pharmacology , Salt Tolerance/drug effects , Sodium Chloride/pharmacology , Amino Acid Sequence , Animals , Colony Count, Microbial , Drug Evaluation, Preclinical , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Hydrophobic and Hydrophilic Interactions , Limulus Test , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred C57BL , Pore Forming Cytotoxic Proteins/chemical synthesis , Pore Forming Cytotoxic Proteins/therapeutic use , Protein Conformation, alpha-Helical , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/blood , Unilamellar LiposomesABSTRACT
Release of lipopolysaccharide (LPS) (endotoxin) from bacteria into the bloodstream may cause serious unwanted stimulation of the host immune system. Some but not all antimicrobial peptides can neutralize LPS-stimulated proinflammatory responses. Salt resistance and serum stability of short antimicrobial peptides can be boosted by adding ß-naphthylalanine to their termini. Herein, significant antiendotoxin effects were observed in vitro and in vivo with the ß-naphthylalanine end-tagged variants of the short antimicrobial peptides S1 and KWWK.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Gram-Negative Bacteria/drug effects , Lipopolysaccharides/antagonists & inhibitors , Antimicrobial Cationic Peptides/chemistry , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , beta-Alanine/analogs & derivatives , beta-Alanine/chemistryABSTRACT
We describe a strategy to boost anticancer activity and reduce normal cell toxicity of short antimicrobial peptides by adding positive charge amino acids and non-nature bulky amino acid ß-naphthylalanine residues to their termini. Among the designed peptides, K4R2-Nal2-S1 displayed better salt resistance and less toxicity to hRBCs and human fibroblast than Nal2-S1 and K6-Nal2-S1. Fluorescence microscopic studies indicated that the FITC-labeled K4R2-Nal2-S1 preferentially binds cancer cells and causes apoptotic cell death. Moreover, a significant inhibition in human lung tumor growth was observed in the xenograft mice treated with K4R2-Nal2-S1. Our strategy provides new opportunities in the development of highly effective and selective antimicrobial and anticancer peptide-based therapeutics.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Lung Neoplasms/drug therapy , Animals , Apoptosis , Cell Line, Tumor , Escherichia coli/drug effects , Humans , Male , Mice, Inbred BALB C , Mice, Nude , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The efficacies of many antimicrobial peptides are greatly reduced in the presence of high salt concentrations therefore limiting their development as pharmaceutical compounds. PEM-2-W5K/A9W, a short Trp-rich antimicrobial peptide developed based on the structural studies of PEM-2, has been shown to be highly active against various bacterial strains with less hemolytic activity. Here, correlations between membrane immersion depth, orientation, and salt-resistance of PEM-2 and PEM-2-W5K/A9W have been investigated via solution structure and paramagnetic resonance enhancement studies. The antimicrobial activities of PEM-2-W5K/A9W and PEM-2 against various bacterial and fungal strains including multidrug-resistant and clinical isolates under high salt conditions were tested. The activities of the salt-sensitive peptide PEM-2 were reduced and diminished at high salt concentrations, whereas the activities of PEM-2-W5K/A9W were less affected. The results indicated that the strong salt-resistance of PEM-2-W5K/A9W may arise from the peptide positioning itself deeply into microbial cell membranes and thus able to disrupt the membranes more efficiently.
Subject(s)
Antimicrobial Cationic Peptides/pharmacology , Sodium Chloride/chemistry , Tryptophan/chemistry , Antimicrobial Cationic Peptides/chemistry , Electron Spin Resonance Spectroscopy , Magnetic Resonance Spectroscopy , Micelles , Microbial Sensitivity Tests , Models, Molecular , Protein ConformationABSTRACT
The efficacies of many antimicrobial peptides are greatly reduced under high salt concentrations, therefore limiting their use as pharmaceutical agents. Here, we describe a strategy to boost salt resistance and serum stability of short antimicrobial peptides by adding the nonnatural bulky amino acid ß-naphthylalanine to their termini. The activities of the short salt-sensitive tryptophan-rich peptide S1 were diminished at high salt concentrations, whereas the activities of its ß-naphthylalanine end-tagged variants were less affected.
