Date Published: December 6, 2012
Publisher: Public Library of Science
Author(s): M. Indriati Hood, Brittany L. Mortensen, Jessica L. Moore, Yaofang Zhang, Thomas E. Kehl-Fie, Norie Sugitani, Walter J. Chazin, Richard M. Caprioli, Eric P. Skaar, Ralph R. Isberg.
Acinetobacter baumannii is an important nosocomial pathogen that accounts for up to 20 percent of infections in intensive care units worldwide. Furthermore, A. baumannii strains have emerged that are resistant to all available antimicrobials. These facts highlight the dire need for new therapeutic strategies to combat this growing public health threat. Given the critical role for transition metals at the pathogen-host interface, interrogating the role for these metals in A. baumannii physiology and pathogenesis could elucidate novel therapeutic strategies. Toward this end, the role for calprotectin- (CP)-mediated chelation of manganese (Mn) and zinc (Zn) in defense against A. baumannii was investigated. These experiments revealed that CP inhibits A. baumannii growth in vitro through chelation of Mn and Zn. Consistent with these in vitro data, Imaging Mass Spectrometry revealed that CP accompanies neutrophil recruitment to the lung and accumulates at foci of infection in a murine model of A. baumannii pneumonia. CP contributes to host survival and control of bacterial replication in the lung and limits dissemination to secondary sites. Using CP as a probe identified an A. baumannii Zn acquisition system that contributes to Zn uptake, enabling this organism to resist CP-mediated metal chelation, which enhances pathogenesis. Moreover, evidence is provided that Zn uptake across the outer membrane is an energy-dependent process in A. baumannii. Finally, it is shown that Zn limitation reverses carbapenem resistance in multidrug resistant A. baumannii underscoring the clinical relevance of these findings. Taken together, these data establish Zn acquisition systems as viable therapeutic targets to combat multidrug resistant A. baumannii infections.
Acinetobacter baumannii is an opportunistic pathogen of growing importance in the hospital setting. Responsible for up to 20 percent of infections in intensive care units worldwide, A. baumannii is particularly problematic due to its propensity to acquire antibiotic resistance determinants –. Moreover, the resistance of A. baumannii to common disinfectants and ability to survive for long periods on dry surfaces make it difficult to eradicate from the hospital environment –. Current multidrug resistance rates range from 48–85% of isolates, with the greatest burden in Asia and Eastern Europe –. Pan resistance is likewise emerging, suggesting that more clinicians will soon be faced with infections for which no effective antimicrobial therapies remain –. Clearly, it is imperative to develop new antimicrobial strategies to combat this emerging threat.
Transition metals occupy an essential niche within biological systems. The essentiality of transition metals to invading bacterial pathogens has been exploited by vertebrate hosts as an innate defense strategy. Most work in the area of nutritional immunity has focused on iron sequestration as a mechanism of host defense; however, it is now appreciated that nutritional immunity includes strategies to withhold other essential metals such as Mn and Zn , . We have demonstrated that Mn and Zn chelation by CP inhibits A. baumannii growth in vitro. We have also determined that CP is abundant in the lungs of A. baumannii-infected mice where it contributes to defense against A. baumannii pulmonary infections. Moreover, we have used CP to elucidate physiological processes that are disrupted by Mn and Zn chelation by screening a transposon library for mutants with increased or decreased susceptibility to CP. Using this screen we identified a Zn acquisition system in A. baumannii and defined its Zn-dependent regulation and its roles in Zn uptake and pathogenesis.