Antibiotic-Resistant Acinetobacter baumannii Is Susceptible to the Novel Iron-Sequestering Anti-infective DIBI In Vitro and in Experimental Pneumonia in Mice
| Autor: | Wangxue Chen, Kimberley A. Savage, Maria del Carmen Parquet, Susan M. Logan, David S. Allan, M. Trisha C. Ang, Bruce E. Holbein |
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| Rok vydání: | 2019 |
| Předmět: |
Acinetobacter baumannii
antibiotic resistance medicine.drug_class Iron Antibiotics Population Virulence Microbial Sensitivity Tests Microbiology Mice 03 medical and health sciences Antibiotic resistance Ciprofloxacin Drug Resistance Multiple Bacterial medicine Animals Pharmacology (medical) education iron acquisition 030304 developmental biology Pharmacology Mice Inbred BALB C 0303 health sciences education.field_of_study biology 030306 microbiology business.industry Pneumonia biology.organism_classification Antimicrobial anti-infective Anti-Bacterial Agents Infectious Diseases Susceptibility Cytokines Female Chemokines business iron sequestration Bacteria medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 63 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Acinetobacter baumannii is a major cause of nosocomial infections especially hospital-acquired pneumonia. This bacterium readily acquires antibiotic resistance traits and therefore, new treatment alternatives are urgently needed. The virulence of A. baumannii linked to iron acquisition suggests a potential for new anti-infectives that target its iron acquisition. DIBI, a 3-hydroxypyridin-4-one chelator, is a purpose-designed, iron-sequestering antimicrobial that has shown promise for treating microbial infection. DIBI was investigated for its in vitro and in vivo activities against clinical A. baumannii isolates. DIBI was inhibitory for all isolates tested with very low MICs (2 μg/ml, equivalent to 0.2 μM), i.e., at or below the typical antibiotic MICs reported for antibiotic-sensitive strains. DIBI inhibition is Fe specific, and it caused an iron-restricted bacterial physiology that led to enhanced antibiotic killing by several discrete antibiotics. DIBI also strongly suppressed recovery growth of the surviving population following antibiotic exposure. A low intranasal dose (11 μmol/kg) of DIBI after intranasal challenge with hypervirulent ciprofloxacin (CIP)-resistant A. baumannii LAC-4 significantly reduced bacterial burdens in mice, and DIBI also suppressed the spread of the infection to the spleen. Treatment of infected mice with CIP alone (20 mg/kg, equivalent to 60 μmol/kg) was ineffective given LAC-4’s CIP resistance, but if combined with DIBI, the treatment efficacy improved significantly. Our evidence suggests that DIBI restricts host iron availability to A. baumannii growing in the respiratory tract, bolstering the host innate iron restriction mechanisms. DIBI has potential as a sole anti-infective or in combination with conventional antibiotics for the treatment of A. baumannii pneumonia. |
| Databáze: | OpenAIRE |
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