Combating virulence of Gram-negative bacilli by OmpA inhibition

Vila-Farrés, Xavier; Parra-Millán, Raquel; Sánchez-Encinales, Viviana; Varese, Monica; Ayerbe-Algaba, Rafael; Bayó‐Puxán, Núria; Guardiola, Salvador; Pachón-Ibáñez, María Eugenia; Kotev, Martin; García, Jesús; Teixidó, Meritxell; Vilà, Jordi; Pachón, Jerónimo; Giralt, Ernest; Smani, Younes

doi:10.1038/s41598-017-14972-y

Cited by 68 publications

(59 citation statements)

References 41 publications

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“…The outer membrane protein A (OmpA) is a beta-barrel porin that is highly conserved among bacterial species, especially Gram-negative bacteria. These authors studied the efficacy of OmpA inhibitors in the prevention of infection both in vitro and in vivo [42]. …”

Section: Vila-farrés Et Almentioning

confidence: 99%

ighting antimicrobial resistance in ESKAPE pathogens

Trastoy¹,

Blasco²,

Bou³

et al. 2018

Fighting Antimicrobial Resistance

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Section: Vila-farrés Et Almentioning

confidence: 99%

ighting antimicrobial resistance in ESKAPE pathogens

Trastoy¹,

Blasco²,

Bou³

et al. 2018

Fighting Antimicrobial Resistance

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“…There is, therefore, an urgent need to find new antimicrobial agents against extensive- and pan-drug-resistant GNB. Two key approaches can help alleviate the problem of antibiotic resistance, firstly targeting of bacterial virulence factors without inhibiting bacterial growth, which can slow the development of drug resistance by reducing the selective pressure on the bacteria (1, 2) and, secondly, by the modulation/regulation of the immune system response to improve the infection development (3, 4). In this way, some studies were focused on the stimulation of the immune system to treat bacterial infections using molecules, including lysophosphatidylcoline as monotherapy and as adjuvant for the antimicrobial treatment (3, 5, 6) or 3’-5’-cyclic diguanylic acid (c-di-GMP) which increase neutrophils protecting against A. baumannii infection (7).…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Miró-Canturri

Ayerbe-Algaba

Pachón

et al. 2020

Preprint

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22The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-23 antimicrobial approaches and/or drugs repurposing to be used as monotherapies or in 24 combination with clinically relevant antibiotics, has become an urgent need. A therapeutic 25 alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune 26 system modulation to improve the infection clearance. We showed that immunocompetent mice 27 infected by Acinetobacter baumannii, Pseudomonas aeruginosa or Escherichia coli in peritoneal 28 sepsis models and treated with tamoxifen at 80 mg/kg/d for three days reduced the release of 29 MCP-1 and its signalling pathway IL-18 and phosphorylated ERK1/2. This reduction of MCP-1 30 induced the reduction of migration of inflammatory monocytes and neutrophils from bone 31 marrow to blood. Indeed, the treatment with tamoxifen in murine peritoneal sepsis models 32 reduced the bacterial load in tissues and blood; and increased the mice survival from 0% to 60-33 100%. Tamoxifen treatment of neutropenic mice infected by these pathogens increased mice 34 survival up to 20-60%. Furthermore, susceptibility and time-kill assays showed that the 35 metabolites of tamoxifen, N-desmethyltamoxifen, hydroxytamoxifen and endoxifen, the three 36 together exhibited MIC 90 values of 16 mg/L and were bactericidal against clinical isolates of A. 37 baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites parallels' an 38 increased membrane permeability of A. baumannii and E. coli without affecting their outer 39 membrane proteins profiles. Together, these data showed that tamoxifen present a therapeutic 40 efficacy against MDR A. baumannii, P. aeruginosa and E. coli in experimental models of 41 infections and can be repurposed as new treatment for GNB infections. 42 43 44 Importance 45Antimicrobial resistance in Gram-negative bacilli (GNB) is a global health treat. Drug 46 repurposing, a novel approach involving the search of new indications for FDA approved drugs 47 is gaining interest. Among them, we found the anti-cancer drug tamoxifen, which presents very 48 promising therapeutic efficacy. The current study showed that tamoxifen presents activity in 49 animal models of infection with MDR Acinetobacter baumannii, Pseudomonas aeruginosa and 50 Escherichia coli by modulating the traffic of innate immune system cells and the antibacterial 51 activity presented by its three major metabolites produced in vivo against these GNB. Our results 52 offer a new candidate to be repurposed to treat severe infections caused by these pathogens. 53 54Infections caused by Gram-negative bacilli (GNB) such as Acinetobacter baumannii, 56 Pseudomonas aeruginosa and Escherichia coli represent an increasing worldwide problem. In 57 2017, the World Health Organization has listed these pathogens as the first antibiotic-resistant 58 "priority pathogens" that pose the greatest threat to human health. There is, therefore, an urgent 59 need to find new an...

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“…Thus, CC strains not only show multi-drug resistance (MDR) phenotypes from the acquisition of different mobile genetic elements enriched in resistance genes, but can also rapidly modify virulence-related surface structures recognized by host defenses as the result of recombination events involving discrete genomic loci (2–6, 9–12). This has left very few treatment options available (2–6, 10, 13) and has led to the alternative search of targets for anti-virulence drugs or vaccines, and in this context a potential candidate is represented by the major A. baumannii outer membrane (OM) protein, OmpA (6, 14–22).…”

Section: Introductionmentioning

confidence: 99%

“…A. baumannii OmpA has been implicated in a multitude of functions that range from structural roles, a slow porin for small hydrophilic nutrients and antimicrobials, and virulence including fibronectin binding, biofilm formation, adhesion to host cells, and cytotoxicity (3, 6, 18, 19, 24, 28–36). It has also been shown to interact with host defenses, inducing innate immune responses, the production of antibodies both in A. baumannii -infected patients and experimentally-infected mice, and to bind antimicrobial peptides via the ELs (14–22, 37). It follows that there are different selective pressures including trade-off mechanisms (23–27, 38) acting on A. baumannii OmpA.…”

Section: Introductionmentioning

confidence: 99%

Microevolution in the major outer membrane protein OmpA ofAcinetobacter baumannii

Viale

Evans

2019

Preprint

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Acinetobacter baumannii is nowadays a relevant nosocomial pathogen characterized by multidrug resistance (MDR) and concomitant difficulties to treat infections. OmpA is the most abundant A. baumannii outer membrane (OM) protein, and is involved in virulence, host cell recognition, biofilm formation, regulation of OM stability, permeability, and antibiotic resistance. OmpA members are two-domain proteins with an N-terminal eight-stranded β-barrel domain with four external loops (ELs) interacting with the environment, and a C-terminal periplasmic domain binding non-covalently to the peptidoglycan. Here, we combined data from genome sequencing, phylogenetic, and multilocus sequence analyses from 242 strains of the Acinetobacter calcoaceticus/Acinetobacter baumannii complex (ACB), 222 from A. baumannii, to explore ompA microevolutionary divergence. Five major ompA variant groups were identified (V1 to V5) comprising 50 different alleles coding for 29 different proteins. Polymorphisms were concentrated in 5 regions corresponding to the four ELs and the C-terminal end, and provided evidence for different intra-genic recombination events. ompA variants were not randomly distributed across the A. baumannii phylogeny, with the most frequent V1a1 allele almost exclusive to clonal complex 1 (CC1) strains and the second most frequent V2a1 allele found in the majority of CC2 strains. Evidence was found for assortative exchanges of ompA alleles not only between different A. baumannii clonal lineages, but also different ACB species. Within A. baumannii ompA non-synonymous substitutions were concentrated in the ELs regions, but were more abundant in the transmembrane regions between different Acinetobacter species. The overall results have implications for A. baumannii evolution, epidemiology, virulence, and vaccine design.ImportanceAcinetobacter baumannii is an increasing MDR threat in nosocomial settings associated with prolonged hospitalization and concomitantly increased healthcare costs. The main A. baumannii OM protein, OmpA, is a multifaceted two-domain protein implicated in host cell recognition and adhesion, cytotoxicity, biofilm formation, and as a slow porin for antibiotics and small hydrophilic nutrients. A. baumannii OmpA has been proposed as a potential target for anti-virulence drugs and as a vaccine candidate. Given the many interactions of this protein with environmental factors including host defenses, it is certainly subjected to many selective pressures. Here, we analyzed the microevolution of this OM protein in the A. baumannii population to obtain clues on the extent to which selection in the clinical setting has shaped this protein. The results provide relevant information on the main causes driving evolution of this protein, with potential implications in A. baumannii epidemiology, virulence, and vaccine design.

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Combating virulence of Gram-negative bacilli by OmpA inhibition

Cited by 68 publications

References 41 publications

ighting antimicrobial resistance in ESKAPE pathogens

ighting antimicrobial resistance in ESKAPE pathogens

Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Microevolution in the major outer membrane protein OmpA ofAcinetobacter baumannii

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