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

Abstract

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.

Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis

“…However, both DFO and DFP have been found to have little or no antimicrobial activity for P. aeruginosa , K. pneumoniae , E. coli , Acinetobacter baumannii and other nosocomial bacterial pathogens [ 42 ]. DIBI has been shown to reduce blood A. baumannii bacterial burdens in infected mice [ 43 ].…”

“…In this regard, DIBI’s relatively short plasma half-life could be beneficial as its plasma levels (and thus, degree of iron chelation) could be better controlled. Additionally, DIBI has exhibited no adverse hematological effects in 14-day chronic systemic toxicity testing with 200 mg/kg daily repeat administrations to rats [ 43 ]. Last but not least, we compared the treatment effects of the different iron chelators after adjusting for similar iron-binding capacity, but the timing after the event and the mode of administration also play an important role in the anti-inflammatory and anti-ROS activity of each drug.…”

Iron Chelation in Local Infection

“…An intranasal dose of DIBI after intranasal challenge with hypervirulent ciprofloxacin (CIP)-resistant A. baumannii significantly reduced bacterial burden in mice. DIBI was shown to restrict host iron availability and work as an anti-infective or in combination with antibiotics for the treatment of A. baumannii pneumonia [ 37 ].…”

Host Innate Immune Responses to Acinetobacter baumannii Infection

“…A. baumannii has also developed redundant and complex iron utilization and regulatory mechanisms (De Leseleuc et al, 2012 , 2014 ; Wong et al, 2017 ; Parquet et al, 2019 ; Runci et al, 2019 ). Iron availability or lack thereof is critical for bacterial growth and host defense (nutrition immunity), respectively; iron may also play an important role in blood dissemination during A. baumannii -associated pneumonia (Parquet et al, 2019 ). A. baumannii also possessed a mumR -mediated transcriptional mechanism for surviving Mn starvation and oxidative stress (Green et al, 2020 ).…”