Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance
ABSTRACT Acinetobacter baumannii is a Gram-negative bacterial pathogen that poses a major health concern due to increasing multidrug resistance. The Gram-negative cell envelope is a key barrier to antimicrobial entry and includes an inner and outer membrane. The maintenance of lipid asymmetry (Mla)...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2024-03-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02804-23 |
| _version_ | 1827150300608200704 |
|---|---|
| author | Hannah R. Noel Sowmya Keerthi Xiaomei Ren Jonathan D. Winkelman Jerry M. Troutman Lauren D. Palmer |
| author_facet | Hannah R. Noel Sowmya Keerthi Xiaomei Ren Jonathan D. Winkelman Jerry M. Troutman Lauren D. Palmer |
| author_sort | Hannah R. Noel |
| collection | DOAJ |
| description | ABSTRACT Acinetobacter baumannii is a Gram-negative bacterial pathogen that poses a major health concern due to increasing multidrug resistance. The Gram-negative cell envelope is a key barrier to antimicrobial entry and includes an inner and outer membrane. The maintenance of lipid asymmetry (Mla) system is the main homeostatic mechanism by which Gram-negative bacteria maintain outer membrane asymmetry. Loss of the Mla system in A. baumannii results in attenuated virulence and increased susceptibility to membrane stressors and some antibiotics. We recently reported two strain variants of the A. baumannii type strain ATCC 17978: 17978VU and 17978UN. Here, ∆mlaF mutants in the two ATCC 17978 strains display different phenotypes for membrane stress resistance, antibiotic resistance, and pathogenicity in a murine pneumonia model. Although allele differences in obgE were previously reported to synergize with ∆mlaF to affect growth and stringent response, obgE alleles do not affect membrane stress resistance. Instead, a single-nucleotide polymorphism (SNP) in the essential gene encoding undecaprenyl pyrophosphate (Und-PP) synthase, uppS, results in decreased enzymatic rate and decrease in total Und-P levels in 17978UN compared to 17978VU. The UppSUN variant synergizes with ∆mlaF to reduce capsule and lipooligosaccharide (LOS) levels, increase susceptibility to membrane stress and antibiotics, and reduce persistence in a mouse lung infection. Und-P is a lipid glycan carrier required for the biosynthesis of A. baumannii capsule, cell wall, and glycoproteins. These findings uncover synergy between Und-P and the Mla system in maintaining the A. baumannii cell envelope and antibiotic resistance.IMPORTANCEAcinetobacter baumannii is a critical threat to global public health due to its multidrug resistance and persistence in hospital settings. Therefore, novel therapeutic approaches are urgently needed. We report that a defective undecaprenyl pyrophosphate synthase (UppS) paired with a perturbed Mla system leads to synthetically sick cells that are more susceptible to clinically relevant antibiotics and show reduced virulence in a lung infection model. These results suggest that targeting UppS or undecaprenyl species and the Mla system may resensitize A. baumannii to antibiotics in combination therapies. This work uncovers a previously unknown synergistic relationship in cellular envelope homeostasis that could be leveraged for use in combination therapy against A. baumannii. |
| first_indexed | 2024-04-25T00:10:05Z |
| format | Article |
| id | doaj.art-5849533742c641baae21e5a4f116aa3e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2025-03-20T21:31:53Z |
| publishDate | 2024-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-5849533742c641baae21e5a4f116aa3e2024-08-11T18:12:03ZengAmerican Society for MicrobiologymBio2150-75112024-03-0115310.1128/mbio.02804-23Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistanceHannah R. Noel0Sowmya Keerthi1Xiaomei Ren2Jonathan D. Winkelman3Jerry M. Troutman4Lauren D. Palmer5Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USADepartment of Chemistry, University of North Carolina Charlotte, Charlotte, North Carolina, USADepartment of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USATrestle LLC, Milwaukee, Wisconsin, USADepartment of Chemistry, University of North Carolina Charlotte, Charlotte, North Carolina, USADepartment of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USAABSTRACT Acinetobacter baumannii is a Gram-negative bacterial pathogen that poses a major health concern due to increasing multidrug resistance. The Gram-negative cell envelope is a key barrier to antimicrobial entry and includes an inner and outer membrane. The maintenance of lipid asymmetry (Mla) system is the main homeostatic mechanism by which Gram-negative bacteria maintain outer membrane asymmetry. Loss of the Mla system in A. baumannii results in attenuated virulence and increased susceptibility to membrane stressors and some antibiotics. We recently reported two strain variants of the A. baumannii type strain ATCC 17978: 17978VU and 17978UN. Here, ∆mlaF mutants in the two ATCC 17978 strains display different phenotypes for membrane stress resistance, antibiotic resistance, and pathogenicity in a murine pneumonia model. Although allele differences in obgE were previously reported to synergize with ∆mlaF to affect growth and stringent response, obgE alleles do not affect membrane stress resistance. Instead, a single-nucleotide polymorphism (SNP) in the essential gene encoding undecaprenyl pyrophosphate (Und-PP) synthase, uppS, results in decreased enzymatic rate and decrease in total Und-P levels in 17978UN compared to 17978VU. The UppSUN variant synergizes with ∆mlaF to reduce capsule and lipooligosaccharide (LOS) levels, increase susceptibility to membrane stress and antibiotics, and reduce persistence in a mouse lung infection. Und-P is a lipid glycan carrier required for the biosynthesis of A. baumannii capsule, cell wall, and glycoproteins. These findings uncover synergy between Und-P and the Mla system in maintaining the A. baumannii cell envelope and antibiotic resistance.IMPORTANCEAcinetobacter baumannii is a critical threat to global public health due to its multidrug resistance and persistence in hospital settings. Therefore, novel therapeutic approaches are urgently needed. We report that a defective undecaprenyl pyrophosphate synthase (UppS) paired with a perturbed Mla system leads to synthetically sick cells that are more susceptible to clinically relevant antibiotics and show reduced virulence in a lung infection model. These results suggest that targeting UppS or undecaprenyl species and the Mla system may resensitize A. baumannii to antibiotics in combination therapies. This work uncovers a previously unknown synergistic relationship in cellular envelope homeostasis that could be leveraged for use in combination therapy against A. baumannii.https://journals.asm.org/doi/10.1128/mbio.02804-23Acinetobacterantibiotic resistancemembrane stressisoprenoidUnd-Pmaintenance of lipid asymmetry |
| spellingShingle | Hannah R. Noel Sowmya Keerthi Xiaomei Ren Jonathan D. Winkelman Jerry M. Troutman Lauren D. Palmer Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance mBio Acinetobacter antibiotic resistance membrane stress isoprenoid Und-P maintenance of lipid asymmetry |
| title | Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance |
| title_full | Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance |
| title_fullStr | Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance |
| title_full_unstemmed | Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance |
| title_short | Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance |
| title_sort | genetic synergy between acinetobacter baumannii undecaprenyl phosphate biosynthesis and the mla system impacts cell envelope and antimicrobial resistance |
| topic | Acinetobacter antibiotic resistance membrane stress isoprenoid Und-P maintenance of lipid asymmetry |
| url | https://journals.asm.org/doi/10.1128/mbio.02804-23 |
| work_keys_str_mv | AT hannahrnoel geneticsynergybetweenacinetobacterbaumanniiundecaprenylphosphatebiosynthesisandthemlasystemimpactscellenvelopeandantimicrobialresistance AT sowmyakeerthi geneticsynergybetweenacinetobacterbaumanniiundecaprenylphosphatebiosynthesisandthemlasystemimpactscellenvelopeandantimicrobialresistance AT xiaomeiren geneticsynergybetweenacinetobacterbaumanniiundecaprenylphosphatebiosynthesisandthemlasystemimpactscellenvelopeandantimicrobialresistance AT jonathandwinkelman geneticsynergybetweenacinetobacterbaumanniiundecaprenylphosphatebiosynthesisandthemlasystemimpactscellenvelopeandantimicrobialresistance AT jerrymtroutman geneticsynergybetweenacinetobacterbaumanniiundecaprenylphosphatebiosynthesisandthemlasystemimpactscellenvelopeandantimicrobialresistance AT laurendpalmer geneticsynergybetweenacinetobacterbaumanniiundecaprenylphosphatebiosynthesisandthemlasystemimpactscellenvelopeandantimicrobialresistance |