Surprising synergy of dual translation inhibition vs. Acinetobacter baumannii and other multidrug-resistant bacterial pathogens

Autor: Ingrid Cornax, Hannah Tsunemoto, Victor Nizet, Michelle Holland, Bryan Hancock, George Sakoulas, Nicholas Dillon, Joe Pogliano
Rok vydání: 2019
Předmět:
Acinetobacter baumannii
0301 basic medicine
Research paper
Antibiotic resistance
Antibiotics
Drug Resistance
Minocycline
Azithromycin
medicine.disease_cause
Mice
0302 clinical medicine
Drug Resistance
Multiple
Bacterial
Medicine
Lung
Translation inhibition
biology
Bacterial
Drug Synergism
General Medicine
Anti-Bacterial Agents
3. Good health
Synergy
Infectious Diseases
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
Pneumonia & Influenza
Public Health and Health Services
Drug
Development of treatments and therapeutic interventions
Infection
Multiple
Acinetobacter Infections
medicine.drug
medicine.drug_class
Clinical Sciences
Microbial Sensitivity Tests
General Biochemistry
Genetics and Molecular Biology
Microbiology
Dose-Response Relationship
03 medical and health sciences
Minimum inhibitory concentration
Animals
Dose-Response Relationship
Drug
Animal
business.industry
Pseudomonas aeruginosa
Prevention
Bacterial cytological profiling
Pneumonia
Antibiotic therapy
biology.organism_classification
Multiple drug resistance
Disease Models
Animal
Emerging Infectious Diseases
Good Health and Well Being
030104 developmental biology
Protein Biosynthesis
Disease Models
Antimicrobial Resistance
business
Zdroj: EBioMedicine
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2019.07.041
Popis: Background Multidrug-resistant (MDR) Acinetobacter baumannii infections have high mortality rates and few treatment options. Synergistic drug combinations may improve clinical outcome and reduce further emergence of resistance in MDR pathogens. Here we show an unexpected potent synergy of two translation inhibitors against the pathogen: commonly prescribed macrolide antibiotic azithromycin (AZM), widely ignored as a treatment alternative for invasive Gram-negative pathogens, and minocycline, among the current standard-of-care agents used for A. baumannii. Methods Media-dependent activities of AZM and MIN were evaluated in minimum inhibitory concentration assays and kinetic killing curves, alone or in combination, both in standard bacteriologic media (cation-adjusted Mueller-Hinton Broth) and more physiologic tissue culture media (RPMI), with variations of bicarbonate as a physiologic buffer. Synergy was calculated by fractional inhibitory concentration index (FICI). Therapeutic benefit of combining AZM and MIN was tested in a murine model of A. baumannii pneumonia. AZM + MIN synergism was probed mechanistically by bacterial cytological profiling (BCP), a quantitative fluorescence microscopy technique that identifies disrupted bacterial cellular pathways on a single cell level, and real-time kinetic measurement of translation inhibition via quantitative luminescence. AZM + MIN synergism was further evaluated vs. other contemporary high priority MDR bacterial pathogens. Findings Although two translation inhibitors are not expected to synergize, each drug complemented kinetic deficiencies of the other, speeding the initiation and extending the duration of translation inhibition as verified by FICI, BCP and kinetic luminescence markers. In an MDR A. baumannii pneumonia model, AZM + MIN combination therapy decreased lung bacterial burden and enhanced survival rates. Synergy between AZM and MIN was also detected vs. MDR strains of Gram-negative Klebsiella pneumoniae and Pseudomonas aeruginosa, and the leading Gram-positive pathogen methicillin-resistant Staphylococcus aureus. Interpretation As both agents are FDA approved with excellent safety profiles, clinical investigation of AZM and MIN combination regimens may immediately be contemplated for optimal treatment of A. baumannii and other MDR bacterial infections in humans. Fund National Institutes of Health U01 AI124326 (JP, GS, VN) and U54 HD090259 (GS, VN). IC was supported by the UCSD Research Training Program for Veterinarians T32 OD017863.
Databáze: OpenAIRE
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