Adaptations of Bacterial Extracellular Vesicles in Response to Antibiotic Pressure
Abstract
1. Introduction: Duality of EVs in Gram-Negative and Gram-Positive Bacteria
1.1. OMVs: Composition, Biogenesis, and Functional Roles
1.2. Structure, Biogenesis, and Roles of MVs in Gram-Positive Bacteria
2. Modulation of Bacterial Vesicles in Response to Antibiotics
2.1. Antibiotic-Induced Changes in OMVs Production in Gram-Negative Bacteria
2.1.1. Secretion of P. aeruginosa-OMVs Under Antibiotic Stress
2.1.2. Antibiotic-Induced Modulation of Escherichia coli-OMVs
2.1.3. OMVs Response to Antibiotics in Other Gram-Negative Bacteria
2.2. Antibiotic-Induced Modulation of MVs in Gram-Positive Bacteria
2.3. Major Enzymes and Protein Classes Involved in OMV-Mediated Antibiotic Resistance
2.3.1. β-Lactamases and Carbapenemases
2.3.2. Efflux Pumps
2.3.3. OMVs Proteome Remodeling
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- Cationic antimicrobial peptide (CAMP) resistance proteins, for example, 4-amino-4-deoxy-L-arabinose transferase and PhoPQ two-component kinase that allows lipid A and OM modifications and are required for resistance to polymyxin and AMPs. Other related enzymes are undecaprenyl phosphate-alpha-L-Ara4N transferase, copper homeostasis protein, and thiol: disulfide interchange protein;
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- OM and envelope remodeling, such as proteins for LPS biosynthesis and O-antigen modification (e.g., KdsA, GmhA, and HldE). The OmpA and others (e.g., OmpX and asmA) showed significant reduction in polymyxin-treated susceptible OMVs;
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- Two-component systems (TCS) CpxA, a protein involved in envelope stress response, is downregulated following the treatment;
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- Protein export and translocation systems, significant changes in Sec and Tat pathways are observed (e.g., the downregulation of SecA, YajC, and YidC), and the downregulation of SurA, a key chaperone for OM protein folding;
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- RNA processing and repair: altered abundance of RNA degradosome proteins (e.g., RNase E, RhlB, and GroEL) and nucleotide excision repair proteins were observed upon polymyxin treatment.
3. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Bacteria | Antibiotic | Evidence | Reference |
---|---|---|---|
P. aeruginosa | Gentamicin | Gentamicin significantly increased the production of OMVs in P. aeruginosa by destabilizing the OM, enriching it with proteins, enzymes, and DNA, suggesting a role for OMVs in the transport of virulence factors during infection. | [147] |
P. aeruginosa | Ciprofloxacin | Ciprofloxacin induces a significant increase in OMV production in P. aeruginosa through the activation of the SOS response, regulated by LexA, enriching the vesicles with proteins involved in antibiotic resistance and virulence, increasing the cytotoxicity and pathogenicity of the bacterium. | [148] |
P. aeruginosa | Meropenem Ciprofloxacin | Combination therapy with meropenem and ciprofloxacin in MDR P. aeruginosa significantly reduces OMV production, attenuates bacterial virulence, and modulates the expression of genes associated with resistance and cellular repair, suggesting a potential benefit in the combined use of these antibiotics. | [149] |
P. aeruginosa | Polymyxin B | P. aeruginosa OMVs regulate intercellular communication by influencing QS and biofilm formation, modulating polymyxin B resistance. | [150] |
E. coli | Gentamicin Amoxicillin/ clavulanate | Exposure to gentamicin and amoxicillin/clavulanate modulates the production and protein composition of OMVs secreted by extraintestinal pathogenic E. coli strains. | [151] |
E. coli | Ciprofloxacin Mitomycin C Fosfomycin Meropenem Polymixin B Rifaximin Tigecycline Azithromycin | Ciprofloxacin and mitomycin C increased OMVs in E. coli EHEC, with an increase in Stx2a toxin and cytotoxicity, whereas fosfomycin, meropenem, and polymyxin B stimulated only OMVs production. Rifaximin, tigecycline, and azithromycin reduced Stx2a and cytotoxicity. | [152] |
E. coli | Ciprofloxacin Mitomycin C Ceftazidime Tigecycline Meropenem Gentamicin Rifaximin | Ciprofloxacin, mitomycin C, ceftazidime, tigecycline, meropenem, gentamicin, and rifaximin stimulated the production of OMVs in tigecycline-resistant E. coli, modifying their size and composition and promoting the spread of the tet (X4) resistance gene. | [153] |
A. baumanni | Imipenem | Imipenem treatment reduced phage proteins but increased β-lactamase OXA-23, enriching A. baumanni OMVs with proteases and membrane proteins (OmpA, OmpW) associated with virulence, biofilm, and antibiotic resistance. | [154] |
S. dysenteriae | Mitomycin C Ciprofloxacin, Norfloxacin Fosfomycin Nalidixic acid | Mitomycin C increased Shiga toxin production in OMVs in S. dysenteriae type 1, whereas ciprofloxacin, norfloxacin, fosfomycin, and nalidixic acid showed no significant effects. OMVs treated with mitomycin C were more numerous, larger (20–150 nm), and highly dense. | [155] |
K. pneumoniae | Meropenem Polymyxin B | In K. pneumoniae KpHCD1, meropenem and polymyxin B increased OMV production, while amikacin decreased it. OMVs contained resistance genes and virulence factors, with protein expression modulated by antibiotics. | [156] |
H. pylori | Clarithromycin Amoxicillin Metronidazole. | OMVs protected H. pylori bacteria from antimicrobial peptides and some antibiotics. OMVs sequestered clarithromycin, reducing its efficacy, but did not protect against amoxicillin or metronidazole. | [157] |
S. maltophilia | Imipenem | Imipenem and QS molecules (DSF) increased OMVs production in S. maltophilia, enriching them with β-lactamases L1 and L2 to counteract antibiotic stress. | [158] |
G. sulfurreducens | Ampicillin Ciprofloxacin | Ampicillin and ciprofloxacin increased the production of OMVs in G. sulfurreducens, altering their morphology and functionality. Ciprofloxacin induced OMVs through explosive cell lysis and phage activation, while ampicillin stimulated the formation of classical OMVs. | [159] |
Bacteria | Antibiotic | Evidence | Reference |
---|---|---|---|
E. faecium | Vancomycin Linezolid | Vancomycin and linezolid increased MV production in E. faecium and altered their protein composition. MVs produced with linezolid showed greater cytotoxicity, while those produced with vancomycin induced a stronger inflammatory response. | [160] |
S. aureus | Mitomycin C Ciprofloxacin Flucloxacillin Ceftaroline Daptomycin | Mitomycin C and ciprofloxacin stimulated MV production in S. aureus through a phage-dependent SOS response mechanism, whereas flucloxacillin and ceftaroline acted independently of phages, damaging the cell wall. The produced MVs protected from daptomycin treatment. | [161] |
S. aureus | Ampicillin | Ampicillin increased the production of MVs derived from S. aureus MRSA, enriching them with β-lactamases and resistance-related proteins, allowing the degradation of the antibiotic and protecting S. aureus without transmitting genetic resistance. | [162] |
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Federica, D.; Cosimato, I.; Salzano, F.; Mensitieri, F.; Andretta, V.; Santoro, E.; Boccia, G.; Folliero, V.; Franci, G. Adaptations of Bacterial Extracellular Vesicles in Response to Antibiotic Pressure. Int. J. Mol. Sci. 2025, 26, 5025. https://doi.org/10.3390/ijms26115025
Federica D, Cosimato I, Salzano F, Mensitieri F, Andretta V, Santoro E, Boccia G, Folliero V, Franci G. Adaptations of Bacterial Extracellular Vesicles in Response to Antibiotic Pressure. International Journal of Molecular Sciences. 2025; 26(11):5025. https://doi.org/10.3390/ijms26115025
Chicago/Turabian StyleFederica, Dell’Annunziata, Ilaria Cosimato, Flora Salzano, Francesca Mensitieri, Vincenzo Andretta, Emanuela Santoro, Giovanni Boccia, Veronica Folliero, and Gianluigi Franci. 2025. "Adaptations of Bacterial Extracellular Vesicles in Response to Antibiotic Pressure" International Journal of Molecular Sciences 26, no. 11: 5025. https://doi.org/10.3390/ijms26115025
APA StyleFederica, D., Cosimato, I., Salzano, F., Mensitieri, F., Andretta, V., Santoro, E., Boccia, G., Folliero, V., & Franci, G. (2025). Adaptations of Bacterial Extracellular Vesicles in Response to Antibiotic Pressure. International Journal of Molecular Sciences, 26(11), 5025. https://doi.org/10.3390/ijms26115025