Abstract
The emergence of multidrug- and extensively drug-resistant Acinetobacter baumannii has made it difficult to treat and control infections caused by this bacterium. Thus, alternatives to conventional antibiotics for management of severe A. baumannii infections is urgently needed. In our previous study, we found that a capsule depolymerase Dpo48 could strip bacterial capsules, and the non-capsuled A. baumannii were significantly decreased in the presence of serum complement in vitro. Here, we further explored its potential as a therapeutic agent for controlling systemic infections caused by extensively drug-resistant A. baumannii. Prior to mammalian studies, the anti-virulence efficacy of Dpo48 was first tested in a Galleria mellonella infection model. Survival rate of Dpo48-pretreated bacteria or Dpo48 treatment group was significantly increased compared to the infective G. mellonella without treatment. Furthermore, the safety and therapeutic efficacy of Dpo48 to mice were evaluated. The mice treated with Dpo48 displayed normal serum levels of TBIL, AST, ALT, ALP, Cr, BUN and LDH, while no significant histopathology changes were observed in tissues of liver, spleen, lung, and kidney. Treatment with Dpo48 could rescue normal and immunocompromised mice from lethal peritoneal sepsis, with the bacterial counts in blood, liver, spleen, lung, and kidney significantly reduced by 1.4–3.3 log colony-forming units at 4 h posttreatment. Besides, the hemolysis and cytotoxicity assays showed that Dpo48 was non-homolytic to human red blood cells and non-toxic to human lung, liver and kidney cell lines. Overall, the present study demonstrated the promising potential of capsule depolymerases as therapeutic agents to prevent antibiotic-resistant A. baumannii infections.
Highlights
Acinetobacter baumannii is an opportunistic pathogen that often causes nosocomial infections, with the highest prevalence noted in immunocompromised and debilitated patients confined to intensive care units (ICUs) (Elhosseiny and Attia, 2018)
The extensively drug-resistant A. baumannii AB1610 was isolated from sputum samples from patients with severe pneumonia in the intensive care unit at 307th Hospital of Chinese People’s Liberation Army, Beijing, China
This A. baumannii strain was identified by 16S ribosomal rRNA gene sequencing, and its antibiotic resistance profile was shown in our previous report (Liu et al, 2019)
Summary
Acinetobacter baumannii is an opportunistic pathogen that often causes nosocomial infections, with the highest prevalence noted in immunocompromised and debilitated patients confined to intensive care units (ICUs) (Elhosseiny and Attia, 2018). Due to the extensive use of broad-spectrum antibiotics, especially carbapenems which are the most potent and reliable β-lactam antibiotics for the treatment of serious A. baumannii infections (GarnachoMontero and Amaya-Villar, 2010), many A. baumannii strains isolated from patient specimens have become highly antibiotic resistant. Colistin has been increasingly used as the last-resort treatment against most carbapenem-resistant A. baumannii. Parental administration of colistin can cause serious side effects including nephrotoxicity and neurotoxicity (Wong et al, 2017). The rapid emergence of colistin-resistant A. baumannii presents huge threats to public health that no effective antibiotics for infections caused by this problematic superbug. There is an urgent need for the development of novel strategies alternative to conventional antibiotics to combat severe A. baumannii infections
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