Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence
Acinetobacter baumannii is often highly drug-resistant and causes severe infections in compromised patients. These infections can be life threatening due to limited treatment options. Copper is inherently antimicrobial and increasing evidence indicates that copper containing formulations may serve a...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-02-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.00016/full |
| _version_ | 1819014741839839232 |
|---|---|
| author | Caitlin L. Williams Heather M. Neu Yonas A. Alamneh Ryan M. Reddinger Anna C. Jacobs Shweta Singh Rania Abu-Taleb Sarah L. J. Michel Daniel V. Zurawski D. Scott Merrell |
| author_facet | Caitlin L. Williams Heather M. Neu Yonas A. Alamneh Ryan M. Reddinger Anna C. Jacobs Shweta Singh Rania Abu-Taleb Sarah L. J. Michel Daniel V. Zurawski D. Scott Merrell |
| author_sort | Caitlin L. Williams |
| collection | DOAJ |
| description | Acinetobacter baumannii is often highly drug-resistant and causes severe infections in compromised patients. These infections can be life threatening due to limited treatment options. Copper is inherently antimicrobial and increasing evidence indicates that copper containing formulations may serve as non-traditional therapeutics against multidrug-resistant bacteria. We previously reported that A. baumannii is sensitive to high concentrations of copper. To understand A. baumannii copper resistance at the molecular level, herein we identified putative copper resistance components and characterized 21 strains bearing mutations in these genes. Eight of the strains displayed a copper sensitive phenotype (pcoA, pcoB, copB, copA/cueO, copR/cusR, copS/cusS, copC, copD); the putative functions of these proteins include copper transport, oxidation, sequestration, and regulation. Importantly, many of these mutant strains still showed increased sensitivity to copper while in a biofilm. Inductively coupled plasma mass spectrometry revealed that many of these strains had defects in copper mobilization, as the mutant strains accumulated more intracellular copper than the wild-type strain. Given the crucial antimicrobial role of copper-mediated killing employed by the immune system, virulence of these mutant strains was investigated in Galleria mellonella; many of the mutant strains were attenuated. Finally, the cusR and copD strains were also investigated in the murine pneumonia model; both were found to be important for full virulence. Thus, copper possesses antimicrobial activity against multidrug-resistant A. baumannii, and copper sensitivity is further increased when copper homeostasis mechanisms are interrupted. Importantly, these proteins are crucial for full virulence of A. baumannii and may represent novel drug targets. |
| first_indexed | 2024-12-21T02:20:40Z |
| format | Article |
| id | doaj.art-7b85bc62f33c4a1a9b6b1ba8f463302b |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-21T02:20:40Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-7b85bc62f33c4a1a9b6b1ba8f463302b2022-12-21T19:19:09ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-02-011110.3389/fmicb.2020.00016501785Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in VirulenceCaitlin L. Williams0Heather M. Neu1Yonas A. Alamneh2Ryan M. Reddinger3Anna C. Jacobs4Shweta Singh5Rania Abu-Taleb6Sarah L. J. Michel7Daniel V. Zurawski8D. Scott Merrell9Department of Microbiology & Immunology, Uniformed Services University, Bethesda, MD, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Baltimore, MD, United StatesWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United StatesWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United StatesWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United StatesWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United StatesWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Baltimore, MD, United StatesWound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United StatesDepartment of Microbiology & Immunology, Uniformed Services University, Bethesda, MD, United StatesAcinetobacter baumannii is often highly drug-resistant and causes severe infections in compromised patients. These infections can be life threatening due to limited treatment options. Copper is inherently antimicrobial and increasing evidence indicates that copper containing formulations may serve as non-traditional therapeutics against multidrug-resistant bacteria. We previously reported that A. baumannii is sensitive to high concentrations of copper. To understand A. baumannii copper resistance at the molecular level, herein we identified putative copper resistance components and characterized 21 strains bearing mutations in these genes. Eight of the strains displayed a copper sensitive phenotype (pcoA, pcoB, copB, copA/cueO, copR/cusR, copS/cusS, copC, copD); the putative functions of these proteins include copper transport, oxidation, sequestration, and regulation. Importantly, many of these mutant strains still showed increased sensitivity to copper while in a biofilm. Inductively coupled plasma mass spectrometry revealed that many of these strains had defects in copper mobilization, as the mutant strains accumulated more intracellular copper than the wild-type strain. Given the crucial antimicrobial role of copper-mediated killing employed by the immune system, virulence of these mutant strains was investigated in Galleria mellonella; many of the mutant strains were attenuated. Finally, the cusR and copD strains were also investigated in the murine pneumonia model; both were found to be important for full virulence. Thus, copper possesses antimicrobial activity against multidrug-resistant A. baumannii, and copper sensitivity is further increased when copper homeostasis mechanisms are interrupted. Importantly, these proteins are crucial for full virulence of A. baumannii and may represent novel drug targets.https://www.frontiersin.org/article/10.3389/fmicb.2020.00016/fullAcinetobacter baumanniimetalcopperpathogenesisGalleria |
| spellingShingle | Caitlin L. Williams Heather M. Neu Yonas A. Alamneh Ryan M. Reddinger Anna C. Jacobs Shweta Singh Rania Abu-Taleb Sarah L. J. Michel Daniel V. Zurawski D. Scott Merrell Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence Frontiers in Microbiology Acinetobacter baumannii metal copper pathogenesis Galleria |
| title | Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence |
| title_full | Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence |
| title_fullStr | Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence |
| title_full_unstemmed | Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence |
| title_short | Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence |
| title_sort | characterization of acinetobacter baumannii copper resistance reveals a role in virulence |
| topic | Acinetobacter baumannii metal copper pathogenesis Galleria |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.00016/full |
| work_keys_str_mv | AT caitlinlwilliams characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT heathermneu characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT yonasaalamneh characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT ryanmreddinger characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT annacjacobs characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT shwetasingh characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT raniaabutaleb characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT sarahljmichel characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT danielvzurawski characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence AT dscottmerrell characterizationofacinetobacterbaumanniicopperresistancerevealsaroleinvirulence |