Antibiotic-Resistant <i>Acinetobacter baumannii</i> Is Susceptible to the Novel Iron-Sequestering Anti-infective DIBI <i>In Vitro</i> and in Experimental Pneumonia in Mice

Abstract

<i>Acinetobacter baumannii</i> 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 <i>A. baumannii</i> 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 <i>in vitro</i> and <i>in vivo</i> activities against clinical <i>A. baumannii</i> 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 <i>A. baumannii</i> 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 <i>A. baumannii</i> 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 <i>A. baumannii</i> pneumonia.