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Review
. 2021 May 6;22(9):4943.
doi: 10.3390/ijms22094943.

Strategies to Tackle Antimicrobial Resistance: The Example of Escherichia coli and Pseudomonas aeruginosa

Giada Antonelli  1   2 , Luigia Cappelli  1   3 , Paolo Cinelli  1   3 , Rossella Cuffaro  1   2 , Benedetta Manca  1   3 , Sonia Nicchi  1   3 , Serena Tondi  1   4 , Giacomo Vezzani  1   3 , Viola Viviani  1   3 , Isabel Delany  1 , Maria Scarselli  1 , Francesca Schiavetti  1
Affiliations
Review

Strategies to Tackle Antimicrobial Resistance: The Example of Escherichia coli and Pseudomonas aeruginosa

Giada Antonelli et al. Int J Mol Sci. .

Abstract

Traditional antimicrobial treatments consist of drugs which target different essential functions in pathogens. Nevertheless, bacteria continue to evolve new mechanisms to evade this drug-mediated killing with surprising speed on the deployment of each new drug and antibiotic worldwide, a phenomenon called antimicrobial resistance (AMR). Nowadays, AMR represents a critical health threat, for which new medical interventions are urgently needed. By 2050, it is estimated that the leading cause of death will be through untreatable AMR pathogens. Although antibiotics remain a first-line treatment, non-antibiotic therapies such as prophylactic vaccines and therapeutic monoclonal antibodies (mAbs) are increasingly interesting alternatives to limit the spread of such antibiotic resistant microorganisms. For the discovery of new vaccines and mAbs, the search for effective antigens that are able to raise protective immune responses is a challenging undertaking. In this context, outer membrane vesicles (OMV) represent a promising approach, as they recapitulate the complete antigen repertoire that occurs on the surface of Gram-negative bacteria. In this review, we present Escherichia coli and Pseudomonas aeruginosa as specific examples of key AMR threats caused by Gram-negative bacteria and we discuss the current status of mAbs and vaccine approaches under development as well as how knowledge on OMV could benefit antigen discovery strategies.

Keywords: Escherichia coli; Pseudomonas aeruginosa; antigen identification; antimicrobial resistance (AMR); monoclonal antibodies (mAbs); outer membrane vesicles (OMV); vaccine.

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Conflict of interest statement

G.A., R.C. and S.T. are PhD students at University of Siena, while L.C., P.C., B.M., S.N. and G.V. are PhD students at the University of Bologna and all participate in a post graduate studentship program at GSK. V.V. was a PhD student at the University of Bologna and participated in a post graduate studentship program at GSK at the time of the study and she is now an employee of Gi Group S.p.A, working as contractor for GSK. I.D., M.S. and F.S. are employee of the GSK group of companies. I.D. reports ownership of GSK stocks. I.D. is listed as inventor on patents on vaccine candidates owned by the GSK group of companies. Bexsero is a trademark owned by or licensed to the GSK group of companies. VA-MENGOC-BC is a trademark of the Finlay Institute, Cuba. MenBvac is a trademark of the Norwegian Institute of Public Health. MeNZB is a trademark of Novartis. Pseudogen is a trademark of Parke-Davis. Aerugen is a trademark of Berna. IMMUNO is a trademark of MediUni. IC43 is a trademark of Valneva. Uro-Vaxom is a trademark of OM Pharma. Urovac is a trademark of Solco Basel. Uromune (MV140) is a trademark of Inmunotek. ExPEC4V is a trademark of Glyco Vaxy. MEDI3902 is a trademark of Medimmune. F598 and AV-0328 are a trademark of Alopexx.

Figures

Figure 1
Figure 1
Outer membrane vesicles (OMV) biogenesis and biomedical applications. (1) The upper panel shows the structure of the OMV originating from the outer membrane of Gram-negative bacteria. In the other panels the wide range of OMV applications is depicted. In particular, (2) OMV can be used as an antigen discovery tool; (3) bacterial OMV are excellent vaccines since they trigger both humoral and cellular immune responses following the immunization; (4) OMV can be decorated on their surface with desired heterologous and homologous protein or saccharide antigens; (5) OMV can also function as cargo delivery of specific luminal recombinant antigens. LPS: lipopolysaccharide; OM: outer membrane; PG: peptidoglycan; IM: inner membrane.
Figure 2
Figure 2
Human vaccines and monoclonal antibodies (mAbs) used to tackle P. aeruginosa infections. In the candidate sections are reported the trademarks and the specific targeted antigens. Pre-clinical and each clinical phase are represented. Red line indicates the phase at which studies were interrupted.
Figure 3
Figure 3
Human vaccines and monoclonal antibodies (mAbs) used to fight E. coli infections. The candidate section describes the trademarks and the specific targeted antigens. Pre-clinical as well as each clinical phase are represented. Arrows reaching dotted line indicate a completed study for that phase, conversely, studies are ongoing.
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