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

Antonelli, Giada; Cappelli, Luigia; Cinelli, Paolo; Cuffaro, Rossella; Manca, Benedetta; Nicchi, Sonia; Tondi, Serena; Vezzani, Giacomo; Viviani, Viola; Delany, Isabel; Scarselli, María; Schiavetti, Francesca

doi:10.3390/ijms22094943

Cited by 20 publications

(17 citation statements)

References 157 publications

(192 reference statements)

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“… This table is based on the following references for vaccines ( Merakou et al., 2018 ; Bianconi et al., 2019 ; Theuretzbacher et al., 2020 ; Sainz-Mejías et al., 2020 ; Micoli et al., 2021 ; Antonelli et al., 2021 ), antibodies ( Lakemeyer et al., 2018 ; Theuretzbacher et al., 2020 ; Adlbrecht et al., 2020 ; Yaeger et al., 2021 ; Zurawski and McLendon, 2020 ), polymyxins ( Li, et al., 2019 ; Theuretzbacher et al., 2020 ; Lepak et al., 2020 ), new antibiotics ( WHO, 2021 ; Dickey et al., 2017 ; Tse et al., 2017 ), new combinations of β-lactam/β-lactamase inhibitor ( WHO, 2021 ; Theuretzbacher et al., 2020 ), phages ( Friman et al., 2016 ; Jault et al., 2019 ; Patil et al., 2021 ), iron metabolism disruption ( Zhang et al., 2021 ; Frei et al., 2020 ), anti-biofilm ( Dickey et al., 2017 ), and other anti-virulence factors ( Dickey et al., 2017 ; Theuretzbacher et al., 2020 ). …”

Section: Discussionmentioning

confidence: 99%

“…A novel approach such as reverse vaccinology combined with genomic technologies has recently been described in P. aeruginosa , identifying potentially surface-exposed immunogenic proteins relevant in pathogenesis ( Bianconi et al., 2019 ). The use of outer membrane vesicles, because it carries many surface antigens that can serve as targets, also represents a promising approach for vaccine development ( Antonelli et al., 2021 ).…”

Section: Vaccines: a Prophylactic Strategy For High-risk Patientsmentioning

confidence: 99%

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What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

Reig

Gouëllec

Bleves

2022

Front. Cell. Infect. Microbiol.

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The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Carbapenem-resistant Pseudomonas aeruginosa (CRPA) are considered “critical-priority” bacteria by the World Health Organization (WHO) since 2017 taking into account criteria such as patient mortality, global burden disease, and worldwide trend of multi-drug resistance (MDR). Indeed P. aeruginosa can be particularly difficult to eliminate from patients due to its combinatory antibiotic resistance, multifactorial virulence, and ability to over-adapt in a dynamic way. Research is active, but the course to a validated efficacy of a new treatment is still long and uncertain. What is new in the anti–P. aeruginosa clinical development pipeline since the 2017 WHO alert? This review focuses on new solutions for P. aeruginosa infections that are in active clinical development, i.e., currently being tested in humans and may be approved for patients in the coming years. Among 18 drugs of interest in December 2021 anti–P. aeruginosa development pipeline described here, only one new combination of β-lactam/β-lactamase inhibitor is in phase III trial. Derivatives of existing antibiotics considered as “traditional agents” are over-represented. Diverse “non-traditional agents” including bacteriophages, iron mimetic/chelator, and anti-virulence factors are significantly represented but unfortunately still in early clinical stages. Despite decade of efforts, there is no vaccine currently in clinical development to prevent P. aeruginosa infections. Studying pipeline anti–P. aeruginosa since 2017 up to now shows how to provide a new treatment for patients can be a difficult task. Given the process duration, the clinical pipeline remains unsatisfactory leading best case to the approval of new antibacterial drugs that treat CRPA in several years. Beyond investment needed to build a robust pipeline, the Community needs to reinvent medicine with new strategies of development to avoid the disaster. Among “non-traditional agents”, anti-virulence strategy may have the potential through novel and non-killing modes of action to reduce the selective pressure responsible of MDR.

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Section: Discussionmentioning

confidence: 99%

Section: Vaccines: a Prophylactic Strategy For High-risk Patientsmentioning

confidence: 99%

What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

Reig

Gouëllec

Bleves

2022

Front. Cell. Infect. Microbiol.

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“…To date, several antigens have been nominated as vaccine candidates 32 , 33 . Although no clinical trials have been conducted for the vaccine candidates against A. baumannii , some vaccine and passive immunization candidates against P. aeruginosa are in phase 2/3 of clinical trials 33 , 34 . Recent advances in active and passive immunization against A. baumannii 33 , 35 – 38 as well as recent clinical trials in the case of P. aeruginosa 33 , 34 revealed that immunization trials are among the most promising resolves against these notorious nosocomial pathogens.…”

Section: Introductionmentioning

confidence: 99%

“…Although no clinical trials have been conducted for the vaccine candidates against A. baumannii , some vaccine and passive immunization candidates against P. aeruginosa are in phase 2/3 of clinical trials 33 , 34 . Recent advances in active and passive immunization against A. baumannii 33 , 35 – 38 as well as recent clinical trials in the case of P. aeruginosa 33 , 34 revealed that immunization trials are among the most promising resolves against these notorious nosocomial pathogens. However, despite numerous efforts carried out to develop effective vaccines against A. baumannii 36 , 38 – 45 and P. aeruginosa 46 – 51 , no approved vaccine is yet available.…”

Section: Introductionmentioning

confidence: 99%

A unique antigen against SARS-CoV-2, Acinetobacter baumannii, and Pseudomonas aeruginosa

Rahbar

Mubarak

Hessami

et al. 2022

Sci Rep

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The recent outbreak of COVID-19 has increased hospital admissions, which could elevate the risk of nosocomial infections, such as A. baumannii and P. aeruginosa infections. Although effective vaccines have been developed against SARS-CoV-2, no approved treatment option is still available against antimicrobial-resistant strains of A. baumannii and P. aeruginosa. In the current study, an all-in-one antigen was designed based on an innovative, state-of-the-art strategy. In this regard, experimentally validated linear epitopes of spike protein (SARS-CoV-2), OmpA (A. baumannii), and OprF (P. aeruginosa) were selected to be harbored by mature OmpA as a scaffold. The selected epitopes were used to replace the loops and turns of the barrel domain in OmpA; OprF311–341 replaced the most similar sequence within the OmpA, and three validated epitopes of OmpA were retained intact. The obtained antigen encompasses five antigenic peptides of spike protein, which are involved in SARS-CoV-2 pathogenicity. One of these epitopes, viz. QTQTNSPRRARSV could trigger antibodies preventing super-antigenic characteristics of spike and alleviating probable autoimmune responses. The designed antigen could raise antibodies neutralizing emerging variants of SARS-CoV-2 since at least two epitopes are consensus. In conclusion, the designed antigen is expected to raise protective antibodies against SARS-CoV-2, A. baumannii, and P. aeruginosa.

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“…In particular, in the case of Shigella, the required genetic modification is the deletion of tolR gene, encoding for a protein involved in the linking of inner and outer membranes (Bereswill et al, 2012;Rossi et al, 2014). GMMA represent an attractive vaccine technology (Rietschel et al, 1991;Schromm et al, 2000;Bereswill et al, 2012;Rossi et al, 2014;Mancini et al, 2020;Micoli and MacLennan, 2020;Antonelli et al, 2021;Fiorino et al, 2021), as they can naturally express the same bacteria antigens or can be carriers of protein antigens or polysaccharides to induce a specific immune response (Bereswill et al, 2012;Kis et al, 2019;Mancini et al, 2021). GMMA stimulate innate immune cells, as they are able to provide innate signals via ligands of toll-like receptors (TLRs) and via pathogen-associated molecular patterns (PAMPs) (Mancini et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Dissecting in Vitro the Activation of Human Immune Response Induced by Shigella sonnei GMMA

Tondi

Clemente

Esposito

et al. 2022

Front. Cell. Infect. Microbiol.

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Generalized Modules for Membrane Antigens (GMMA) are outer membrane exosomes purified from Gram-negative bacteria genetically mutated to increase blebbing and reduce risk of reactogenicity. This is commonly achieved through modification of the lipid A portion of lipopolysaccharide. GMMA faithfully resemble the bacterial outer membrane surface, and therefore represent a powerful and flexible platform for vaccine development. Although GMMA-based vaccines have been demonstrated to induce a strong and functional antibody response in animals and humans maintaining an acceptable reactogenicity profile, the overall impact on immune cells and their mode of action are still poorly understood. To characterize the GMMA-induced immune response, we stimulated human peripheral blood mononuclear cells (hPBMCs) with GMMA from Shigella sonnei. We studied GMMA both with wild-type hexa-acylated lipid A and with the corresponding less reactogenic penta-acylated form. Using multicolor flow cytometry, we assessed the activation of immune cell subsets and we profiled intracellular cytokine production after GMMA stimulation. Moreover, we measured the secretion of thirty cytokines/chemokines in the cell culture supernatants. Our data indicated activation of monocytes, dendritic, NK, B, and γδ T cells. Comparison of the cytokine responses showed that, although the two GMMA have qualitatively similar profiles, GMMA with modified penta-acylated lipid A induced a lower production of pro-inflammatory cytokines/chemokines compared to GMMA with wild-type lipid A. Intracellular cytokine staining indicated monocytes and dendritic cells as the main source of the cytokines produced. Overall, these data provide new insights into the activation of key immune cells potentially targeted by GMMA-based vaccines.

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

Cited by 20 publications

References 157 publications

What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

A unique antigen against SARS-CoV-2, Acinetobacter baumannii, and Pseudomonas aeruginosa

Dissecting in Vitro the Activation of Human Immune Response Induced by Shigella sonnei GMMA

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