Maria Loreto Incandela

University of Pavia

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Ana Ribeiro

University of Pavia

Giovanna Riccardi

University of Pavia

Maria Rosalia Pasca

University of Pavia

Giorgia Mori

University of Sydney

Renato Fani

University of Florence

Silvia Buroni

University of Pavia

Claudia Dalla Valle

University of Perugia

Giulia Degiacomi

University of Pavia

P. Marone

Istituti di Ricovero e Cura a Carattere Scientifico

M. Gramegna

American Sentinel University

Cooperative Institutions

University of Pavia

Istituti di Ricovero e Cura a Carattere Scientifico

Institut Pasteur Korea

Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani

Policlinico San Matteo Fondazione

University of Florence

University of Milan

Centre National de la Recherche Scientifique

St. Vincent's University Hospital

Virginia Commonwealth University

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Analogous Mechanisms of Resistance to Benzothiazinones and Dinitrobenzamides in Mycobacterium smegmatis

PLoS ONE (2011)

Ana Ribeiro Giulia Degiacomi Fanny Ewann Silvia Buroni Maria Loreto Incandela

Tuberculosis is still a leading cause of death worldwide. The selection and spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Recently, two different classes of chemical series, the benzothiazinones (BTZ) and the dinitrobenzamide (DNB) derivatives have been found to be highly active against M. tuberculosis, including XDR-TB strains. The target of BTZs is DprE1 protein which works in concert with DprE2 to form the heteromeric decaprenylphosphoryl-β-D-ribose 2′-epimerase, involved in Decaprenyl-Phospho-Arabinose (DPA) biosynthesis. Interestingly, it has been shown that the DNBs block the same pathway thus suggesting that both drugs could share the same target. Moreover, in Mycobacterium smegmatis the overexpression of the NfnB nitroreductase led to the inactivation of the BTZs by reduction of a critical nitro-group to an amino-group. In this work several spontaneous M. smegmatis mutants resistant to DNBs were isolated. Sixteen mutants, showing high levels of DNB resistance, exhibited a mutation in the Cys394 of DprE1. Using fluorescence titration and mass spectrometry it has been possible to monitor the binding between DprE1 and DNBs, achieving direct evidence that MSMEG_6382 is the cellular target of DNBs in mycobacteria. Additionally, M. smegmatis mutants having low levels of resistance to DNBs harbor various mutations in MSMEG_6503 gene encoding the transcriptional repressor of the nitroreductase NfnB. By LC/MS2 analysis it has been demonstrated that NfnB is responsible for DNB inactivation. Taken together, our data demonstrate that both DNB and BTZ drugs share common resistance mechanisms in M. smegmatis.

Mycobacterium smegmatis

Nitroreductase

10.1371/journal.pone.0026675

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Evaluation of Fluoroquinolone Resistance Mechanisms inPseudomonas aeruginosaMultidrug Resistance Clinical Isolates

Microbial Drug Resistance (2011)

Maria Rosalia Pasca Claudia Dalla Valle Ana Ribeiro Silvia Buroni Maria Cristiana Papaleo

Efflux transporters have a considerable role in the multidrug resistance (MDR) of Pseudomonas aeruginosa, an important nosocomial pathogen. In this study, 45 P. aeruginosa clinical strains, with an MDR phenotype, have been isolated in a hospital of Northern Italy and characterized to identify the mechanisms responsible for their fluoroquinolone (FQ) resistance. These isolates were analyzed for clonal similarity, mutations in genes encoding the FQ targets, overexpression of specific Resistance Nodulation-cell Division efflux pumps, and search for mutations in their regulatory genes. The achieved results suggested that the mutations in genes encoding ciprofloxacin targets represented the main mechanism of FQ resistance of these strains; 97.8% of these isolates showed mutations in gyrA, 28.9% in gyrB, 88.9% in parC, and 6.7% in parE. Another mechanism of resistance was overexpression of the efflux pumps in some representative strains. In particular, overexpression of MexXY-OprM drug transporter was found in five isolates, whereas overexpression of MexCD-OprJ was detected in two isolates; surprisingly, in one of these last two isolates, also overexpression of MexAB-OprM pump was identified.

Efflux

10.1089/mdr.2011.0019

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DprE1, a new taxonomic marker in mycobacteria

FEMS Microbiology Letters (2013)

Maria Loreto Incandela Elena Perrin Marco Fondi Ana Ribeiro Giorgia Mori

Among the species of the Mycobacterium genus, more than 50 have been recognized as human pathogens. In spite of the different diseases caused by mycobacteria, the interspecies genetic similarity ranges from 94% to 100%, and for some species, this value is higher than in other bacteria. Consequently, it is important to understand the relationships existing among mycobacterial species. In this context, the possibility to use Mycobacterium tuberculosis dprE1 gene as new phylogenetic/taxonomic marker has been explored. The dprE1 gene codes for the target of benzothiazinones, belonging to a very promising class of antitubercular drugs. Mutations in cysteine 387 of DprE1 are responsible for benzothiazinone resistance. The DprE1 tree, obtained with 73 amino acid sequences of mycobacterial species, revealed that concerning the benzothiazinone sensitivity/resistance, it is possible to discriminate two clusters. To validate it, a concatamer obtained from the amino acid sequences of nine mycobacterial housekeeping genes was performed. The concatamer revealed that there is no separation between the benzothiazinone-susceptible and benzothiazinone-resistant species; consequently, this parameter is not linked to the phylogeny. DprE1 tree might represent a good taxonomic marker for the assignment of a mycobacterial isolate to a species. Moreover, the concatamer represents a good reference phylogeny for the Mycobacterium genus.

Housekeeping gene

10.1111/1574-6968.12246

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Citations (13)