Abstract
Acinetobacter baumannii often causes serious nosocomial infections. Because of its serious drug resistance problems, complex drug resistance mechanism, and rapid adaptation to antibiotics, it often shows pan-drug resistance and high fatality rates, which represent great challenges for clinical treatment. Therefore, identifying new ways to overcome antibiotic resistance is particularly important. In this study, mice immunized with A. baumannii outer membrane vesicles (AbOMVs) produced high IgG levels for a long time, and this antiserum significantly increased the small molecule intracellular aggregation rate and concentrations. In vitro experiments demonstrated that the combined used of anti-AbOMV serum and quinolone antibiotics significantly increased the sensitivity of the bacteria to these antibiotics. Mouse sepsis model experiments demonstrated that delivery of these antibodies using both active and passive immunization strategies significantly improved the susceptibility to quinolone antibiotics, improved the survival rate of mice infected with A. baumannii, and reduced the bacterial load in the organs. In a pneumonia model, the combination of serum anti-AbOMVs and levofloxacin improved levofloxacin sensitivity, which significantly reduced the bacterial loads in the lung and spleen compared with those of the antibiotic or antibody alone. This combination also significantly reduced lung inflammatory cell infiltration and inflammatory cytokine aggregation. In this study, the main protein targets that bound to these antibodies were identified. Structural modeling showed that seven of the proteins were porins. Therefore, we speculated that the anti-AbOMV antibodies mainly improved the intracellular aggregation of antibiotics by affecting porins, thus improving susceptibility to quinolone antibiotics. This study provides a method to improve susceptibility to existing antibiotics and a novel idea for the prevention and treatment of pan-drug-resistant A. baumannii.
Highlights
Acinetobacter baumannii is widely found in nature and is prone to causing infections in the skin, respiratory tract, and urinary system
The vesicles secreted by PDR A. baumannii Ab112 were collected, and the morphology of the A. baumannii outer membrane vesicles (AbOMVs) were observed under a transmission electron microscope in a random field of view (Figure 1A)
The IgG level in the 2 μg dose group was significantly higher than that in the 0.2 μg dose group; the 2 μg dose group sustained a high IgG antibody level for up to 40 weeks, whereas the IgG level in the 0.2 μg dose group had begun to decrease by 15 weeks (Figure 1C). These results showed that the AbOMV vaccine could rapidly induce a high and prolonged IgG response
Summary
Acinetobacter baumannii is widely found in nature and is prone to causing infections in the skin, respiratory tract, and urinary system. It is an important conditional pathogen in hospitals (An and Su, 2018). The A. baumannii infection rate continues to rise with the widespread use of antibacterial drugs and has increased in various invasive procedures, and this bacteria has become the main pathogen responsible for nosocomial infections. The resistance mechanisms of A. baumannii include inhibition of membrane permeability, efflux pumps, druginactivating enzymes, and drug target changes. Bacteria can initiate efflux systems and prevent antibacterial drugs from reaching their effective therapeutic concentrations in the bacteria, which can escape the bactericidal effects of the antibiotics (Smani et al, 2014; Krishnamoorthy et al, 2017)
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