Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance

• Published in: mBio 2024-03, Vol.15 (3), p.e0280423
• Main Authors: Noel, Hannah R, Keerthi, Sowmya, Ren, Xiaomei, Winkelman, Jonathan D, Troutman, Jerry M, Palmer, Lauren D
• Format: Article
• Language: English
• Subjects: Acinetobacter; Acinetobacter baumannii; Animals; Anti-Bacterial Agents - pharmacology; antibiotic resistance; Bacteriology; Cell Wall; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; isoprenoid; maintenance of lipid asymmetry; membrane stress; Mice; Polyisoprenyl Phosphates; Research Article; Und-P
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02804-23

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 results in attenuated virulence and increased susceptibility to membrane stressors and some antibiotics. We recently reported two strain variants of the type strain ATCC 17978: 17978VU and 17978UN. Here, ∆ 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 were previously reported to synergize with ∆ to affect growth and stringent response, alleles do not affect membrane stress resistance. Instead, a single-nucleotide polymorphism (SNP) in the essential gene encoding undecaprenyl pyrophosphate (Und-PP) synthase, , results in decreased enzymatic rate and decrease in total Und-P levels in 17978UN compared to 17978VU. The UppS variant synergizes with ∆ 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 capsule, cell wall, and glycoproteins. These findings uncover synergy between Und-P and the Mla system in maintaining the cell envelope and antibiotic resistance.IMPORTANCE 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 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 .