Aurian Maleki

Background:  Rising antibiotic resistance in critical care settings has prompted research into nongenetic mechanisms that allow susceptible bacteria to survive previously lethal antibiotic exposures. A factor that has emerged in recent studies is the role of outer membrane vesicles (OMVs)—nanosized secretions from both Gram-negative and Gram-positive bacteria—carrying enzymes, membrane proteins, and genetic material. OMVs have been shown to facilitate inter-bacterial protection against β-lactam antibiotics and likewise contribute to treatment failure in polymicrobial infections. While traditional resistance mechanisms have focused on localized gene transfer via conjugation or plasmid uptake, OMV-mediated resistance introduces a novel mechanism in which bacteria can gain transient or permanent resistance phenotypes through protein and enzyme transfers, bypassing direct genetic exchange¹⁻³.

Objective:  This review analyzed a collection of recent publications exploring how OMVs derived from multidrug-resistant bacteria contribute to β-lactam antibiotic resistance, with a particular focus on their effects within cohabiting susceptible bacteria and clinical implications for severe infections.

Search Methods:  A literature search was conducted using PubMed from 2017 to 2025 with the following keywords and terms: “outer membrane vesicles,” “β-lactam resistance,” “horizontal gene transfer,” “biofilm,” and “Gram-positive vesicles.” Articles selected for analysis included studies with in vitro and in vivo evidence of OMV-mediated resistance mechanisms and clinical/translational implications.  A subsequent article showed that OMVs specifically from Acinetobacter baumannii delivered the OXA-24 carbapenemase gene to susceptible strains, conferring permanent resistance without relying on plasmid transfer³. OMVs from Klebsiella pneumoniae carried both β-lactamases and virulence proteins that altered cytokine profiles in host immune cells, promoting immune evasion and bacterial persistence⁴. Additional evidence showed that OMVs strengthen biofilm structure and shield bacteria in polymicrobial settings, including ventilator-associated pneumonia and wound infections⁵. The mechanism of OMV biogenesis in Gram-negative bacteria has been linked to disruptions in membrane lipid asymmetry via the VacJ/Yrb transport system⁶, while Gram-positive bacteria utilize regulated peptidoglycan remodeling for vesicle release⁵. A more recent study using Pseudomonas aeruginosa models showed that both planktonic and biofilm-derived OMVs can also mediate horizontal gene transfer of resistance plasmids, further supporting the role of OMVs in interbacterial communication, including through primitive gene transfer sequences⁷.

Conclusion:  OMVs represent an emerging mechanism of antibiotic resistance that can bypass traditional gene transfer mechanisms and potentially underlie the persistence of infection in critically ill patients. Their ability to disseminate resistance enzymes, genetic material, and virulence factors raises the concern for resistant polymicrobial infections and diagnostic misinterpretation. Targeting OMV production or function may offer a novel adjunctive strategy in treating multidrug-resistant infections, particularly in sepsis and hospital-acquired pneumonia. Future research and additional funding should focus on OMV-inhibiting compounds, vesicle-targeted adjuvants, and diagnostics capable of detecting OMV-associated resistance, including in standard hospital laboratories which largely these diagnostic elements.

Work Cited:

1. Kim SW, Park SB, Im SP, et al. Outer membrane vesicles from β-lactam-resistant Escherichia coli enable the survival of β-lactam-susceptible coli in the presence of βlactam antibiotics. Sci Rep. 2018;8(1):5402. doi:10.1038/s41598-018-23656-0
2. Lee AR, Park SB, Kim SW, et al. Membrane vesicles from antibiotic-resistant Staphylococcus aureus transfer antibiotic resistance to antibiotic-susceptible Escherichia coli. J Appl Microbiol. 2022;132(4):2746-2759. doi:10.1111/jam.15449
3. Rumbo C, Fernández-Moreira E, Merino M, et al. Horizontal transfer of the OXA-24 carbapenemase gene via outer membrane vesicles: a new mechanism of dissemination of carbapenem resistance genes in Acinetobacter baumannii. Antimicrob Agents Chemother. 2011;55(7):3084-3090. doi:10.1128/AAC.00929-10
4. Li L, Xu X, Cheng P, et al. Klebsiella pneumoniae derived outer membrane vesicles mediated bacterial virulence, antibiotic resistance, host immune responses and clinical applications. Virulence. 2025;16(1). doi:10.1080/21505594.2025.2449722
5. Liu X, Xiao J, Wang S, et al. Research progress on bacterial membrane vesicles and antibiotic resistance. Int J Mol Sci. 2022;23(19):11553. doi:10.3390/ijms231911553
6. Roier S, Zingl FG, Cakar F, et al. A novel mechanism for the biogenesis of outer membrane vesicles in Gram-negative bacteria. Nat Commun. 2016;7:10515. doi:10.1038/ncomms10515
7. Johnston C, Carroll C, Latimer J, et al. Planktonic and biofilm-derived Pseudomonas aeruginosa outer membrane vesicles facilitate horizontal gene transfer of plasmid DNA. Front Microbiol. 2023;14:1123456. doi:10.3389/fmicb.2023.1