Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

Pacios, Olga; Blasco, Lucía; Bleriot, Inés; Fernández-García, Laura; Bardanca, Mónica González; Ambroa, Antón; López, María; Bou, Germán; Tomás, María

doi:10.3390/antibiotics9020065

Cited by 158 publications

(118 citation statements)

References 105 publications

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“…Clinicians are facing these bacterial species more and more, as they are often responsible of severe nosocomial infections, unfortunately resisting most of the current antibiotic therapies [ 2 , 3 ]. The preclinical antibacterial pipeline needs to be continually replenished by implementing novel approaches to tackle this problem [ 4 , 5 ]; many of these approaches often involve identification and characterization of naturally produced antimicrobial compounds to be developed as potential antibiotics [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens

Sola

Mardirossian

Beckert

et al. 2020

IJMS

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Proline-rich antimicrobial peptides (PrAMPs) may be a valuable weapon against multi-drug resistant pathogens, combining potent antimicrobial activity with low cytotoxicity. We have identified novel PrAMPs from five cetacean species (cePrAMPs), and characterized their potency, mechanism of action and in vitro cytotoxicity. Despite the homology between the N-terminal of cePrAMPs and the bovine PrAMP Bac7, some differences emerged in their sequence, activity spectrum and mode of action. CePrAMPs with the highest similarity with the Bac7(1-35) fragment inhibited bacterial protein synthesis without membrane permeabilization, while a second subgroup of cePrAMPs was more membrane-active but less efficient at inhibiting bacterial translation. Such differences may be ascribable to differences in presence and positioning of Trp residues and of a conserved motif seemingly required for translation inhibition. Unlike Bac7(1-35), which requires the peptide transporter SbmA for its uptake, the activity of cePrAMPs was mostly independent of SbmA, regardless of their mechanism of action. Two peptides displayed a promisingly broad spectrum of activity, with minimal inhibiting concentration MIC ≤ 4 µM against several bacteria of the ESKAPE group, including Pseudomonas aeruginosa and Enterococcus faecium. Our approach has led us to discover several new peptides; correlating their sequences and mechanism of action will provide useful insights for designing optimized future peptide-based antibiotics.

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Section: Introductionmentioning

confidence: 99%

Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens

Sola

Mardirossian

Beckert

et al. 2020

IJMS

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“…Moreover, endolysins have been recognized in the US "National Action Plan for Combating Antibiotic-resistant Bacteria" 24 , which identified the use of "phage-derived lysins to kill specific bacteria while preserving the microbiota" as a key strategy to reduce the development of antimicrobial resistance due to www.nature.com/scientificreports www.nature.com/scientificreports/ the absence of toxicity in human cells 25,26 . Moreover, some endolysins have been found to display activity against sub-populations of microbes 27,28 extracted from biofilm [29][30][31] and to be useful in other innovative treatments.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens

Blasco

Ambroa

Trastoy

et al. 2020

Sci Rep

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The emergence of multidrug resistant (MDR) pathogenic bacteria is jeopardizing the value of antimicrobials, which had previously changed the course of medical science. In this study, we identified endolysins ElyA1 and ElyA2 (GH108-PG3 family), present in the genome of bacteriophages Ab1051Φ and Ab1052Φ, respectively. The muralytic activity of these endolysins against MDR clinical isolates (Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae) was tested using the turbidity reduction assay. Minimal inhibitory concentrations (MICs) of endolysin, colistin and a combination of endolysin and colistin were determined, and the antimicrobial activity of each treatment was confirmed by time kill curves. Endolysin ElyA1 displayed activity against all 25 strains of A. baumannii and P. aeruginosa tested and against 13 out of 17 strains of K. pneumoniae. Endolysin ElyA2 did not display any such activity. The combined antimicrobial activity of colistin and ElyA1 yielded a reduction in the colistin MIC for all strains studied, except K. pneumoniae. These results were confirmed in vivo in G. mellonella survival assays and in murine skin and lung infection models. In conclusion, combining colistin (1/4 MIC) with the new endolysin ElyA1 (350 µg) enhanced the bactericidal activity of colistin in both in vitro and in vivo studies. This will potentially enable reduction of the dose of colistin used in clinical practice.

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“…There is an urgent need to nd therapeutic interventions by repurposing existing drugs for possible use against SARS-CoV-2 by targeting the proteins encoded by the viral genome. Several studies are ongoing, including clinical trials, on repurposing of approved drugs (Pacios et al, 2020). The major focus of research interest has been on the spike glycoprotein and the proteases.…”

Section: Discussionmentioning

confidence: 99%

Repurposing drugs for treatment of SARS-CoV-2 infection: Computational design insights into mechanisms of action

Kandwal

Fayne

2020

Preprint

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The COVID-19 pandemic has negatively affected human life globally. It has led to economic crises and health emergencies across the world, spreading rapidly among the human population and has caused many deaths. Currently, there are no treatments available for COVID-19 so there is an urgent need to develop therapeutic interventions that could be used against the novel coronavirus infection. In this research, we used computational drug design technologies to repurpose existing drugs as inhibitors of SARS-CoV-2 viral proteins. The Broad Institute’s Drug Repurposing Hub consists of in-development/approved drugs and was computationally screened to identify potential hits which could inhibit protein targets encoded by the SARS-CoV-2 genome. By virtually screening the Broad collection, using rationally designed pharmacophore features, we identified molecules which may be repurposed against viral nucleocapsid and non-structural proteins. The pharmacophore features were generated after careful visualisation of the interactions between co-crystalised ligands and the protein binding site. The ChEMBL database was used to determine the compound’s level of inhibition of SARS-CoV-2 and correlate the predicted viral protein target with whole virus in vitro data. The results from this study may help to accelerate drug development against COVID-19 and the hit compounds should be progressed through further in vitro and in vivo studies on SARS-CoV-2.

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Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

Cited by 158 publications

References 105 publications

Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens

Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens

In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens

Repurposing drugs for treatment of SARS-CoV-2 infection: Computational design insights into mechanisms of action

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