1. A global regulatory system links virulence and antibiotic resistance to envelope homeostasis in Acinetobacter baumannii
- Author
-
Nadav J. Mortman, Ralph R. Isberg, Albert K. Tai, Edward Geisinger, and Germán Vargas-Cuebas
- Subjects
Acinetobacter baumannii ,0301 basic medicine ,Polymers ,Gene Expression ,Drug resistance ,Transcriptome ,Mice ,Antibiotics ,Drug Resistance, Multiple, Bacterial ,Medicine and Health Sciences ,Transcriptional regulation ,Homeostasis ,Cell Cycle and Cell Division ,lcsh:QH301-705.5 ,Regulation of gene expression ,Virulence ,Antimicrobials ,Drugs ,Anti-Bacterial Agents ,Chemistry ,Macromolecules ,Lytic cycle ,Cell Processes ,Physical Sciences ,Female ,Cellular Structures and Organelles ,Research Article ,Acinetobacter Infections ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,Materials by Structure ,DNA transcription ,Materials Science ,030106 microbiology ,Immunology ,Microbial Sensitivity Tests ,Biology ,Microbiology ,beta-Lactam Resistance ,beta-Lactamases ,03 medical and health sciences ,Cell Walls ,Antibiotic resistance ,Bacterial Proteins ,Microbial Control ,Virology ,Drug Resistance, Bacterial ,Hypersensitivity ,Genetics ,Animals ,Molecular Biology ,Alleles ,Pharmacology ,Biology and Life Sciences ,Cell Biology ,Gene Expression Regulation, Bacterial ,Peptidoglycans ,Polymer Chemistry ,biology.organism_classification ,Mice, Inbred C57BL ,lcsh:Biology (General) ,Antibiotic Resistance ,Biofilms ,Clinical Immunology ,Parasitology ,Antimicrobial Resistance ,Clinical Medicine ,lcsh:RC581-607 - Abstract
The nosocomial pathogen Acinetobacter baumannii is a significant threat due to its ability to cause infections refractory to a broad range of antibiotic treatments. We show here that a highly conserved sensory-transduction system, BfmRS, mediates the coordinate development of both enhanced virulence and resistance in this microorganism. Hyperactive alleles of BfmRS conferred increased protection from serum complement killing and allowed lethal systemic disease in mice. BfmRS also augmented resistance and tolerance against an expansive set of antibiotics, including dramatic protection from β-lactam toxicity. Through transcriptome profiling, we showed that BfmRS governs these phenotypes through global transcriptional regulation of a post-exponential-phase-like program of gene expression, a key feature of which is modulation of envelope biogenesis and defense pathways. BfmRS activity defended against cell-wall lesions through both β-lactamase-dependent and -independent mechanisms, with the latter being connected to control of lytic transglycosylase production and proper coordination of morphogenesis and division. In addition, hypersensitivity of bfmRS knockouts could be suppressed by unlinked mutations restoring a short, rod cell morphology, indicating that regulation of drug resistance, pathogenicity, and envelope morphogenesis are intimately linked by this central regulatory system in A. baumannii. This work demonstrates that BfmRS controls a global regulatory network coupling cellular physiology to the ability to cause invasive, drug-resistant infections., Author summary Infections with the hospital-acquired bacterium Acinetobacter baumannii are highly difficult to treat. The pathogen has evolved multiple lines of defense against antimicrobial stress, including a barrier-forming cell envelope as well as control systems that respond to antimicrobial stresses by enhancing antibiotic resistance and virulence. Here, we uncovered the role of a key stress-response system, BfmRS, in controlling the transition of A. baumannii to a state of heightened resistance and virulence. We show that BfmRS enhances pathogenicity in mammalian hosts, and augments the ability to grow in the presence of diverse antibiotics and tolerate transient, high-level antibiotic exposures. Connected to these effects is the ability of BfmRS to globally reprogram gene expression and control multiple pathways that build, protect, and shape the cell envelope. Moreover, we determined that resistance-enhancing mutations bypassing the need for BfmRS also modulate envelope- and morphology-associated pathways, further linking control of physiology with resistance in A. baumannii. This work uncovers a global control circuit that shifts cellular physiology in ways that promote hospital-associated disease, and points to inhibition of this circuit as a potential strategy for disarming the pathogen.
- Published
- 2018