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Background Multidrug- (MDR) and extensively drug resistant (XDR) tuberculosis (TB) presents a challenge to disease control and elimination goals. In Lisbon, Portugal, specific and successful XDR-TB strains have been found in circulation for almost two decades. Results In the present study we have genotyped and sequenced the genomes of 56 Mycobacterium tuberculosis isolates recovered mostly from Lisbon. The genotyping data revealed three major clusters associated with MDR-TB, two of which are associated with XDR-TB. Whilst the genomic data contributed to elucidate the phylogenetic positioning of circulating MDRTB strains, showing a high predominance of a single SNP cluster group 5. Furthermore, a genome-wide phylogeny analysis from these strains, together with 19 publicly available genomes of Mycobacterium tuberculosis clinical isolates, revealed two major clades responsible for M/XDR-TB in the region: Lisboa3 and Q1 (LAM). The data presented by this study yielded insights on microevolution and identification of novel compensatory mutations associated with rifampicin resistance in rpoB and rpoC. The screening for other structural variations revealed putative clade-defining variants. One deletion in PPE41, found among Lisboa3 isolates, is proposed to contribute to immune evasion and as a selective advantage. Insertion sequence (IS) mapping has also demonstrated the role of IS6110 as a major driver in mycobacterial evolution by affecting gene integrity and regulation. Conclusions Globally, this study contributes with novel genome-wide phylogenetic data and has led to the identification of new genomic variants that support the notion of a growing genomic diversity facing both setting and host adaptation. [ABSTRACT FROM AUTHOR]

Clin Microbiol Infect 2011; 17: 1397-1402 Abstract Multidrug-resistance and extensive drug-resistance pose a serious threat to tuberculosis management in Portugal. The country has high TB incidence rates in comparison with other European Union countries, with the Lisbon Health Region being one of the most affected. In the present study we have analysed a convenience sample of 3025 Mycobacterium tuberculosis clinical isolates, recovered over a 6-year period (2001-2006) in the Lisbon Health Region, regarding drug-resistance both to first-line and second-line drugs. Moreover, 100 of these isolates were also genotyped by 12-loci Mycobacterial Interspersed Repetitive Unit - Variable Number of Tandem Repeats (MIRU-VNTR) analysis. We have compared each year and observed the existence of 22 different resistance profiles, with MDR-TB rates ranging between 9.9% and 15.2% and XDR-TB rates, relative to the number of MDR-TB isolates, between 44.3% and 66.1% (excluding 1 year here considered as an outlier). A steady increase in the fraction of MDR-TB isolates resistant to all first-line drugs was also noticed. The genotyping analysis of MDR-TB isolates revealed six clusters, of which three (Lisboa3, Lisboa4 and Q1) were related to XDR-TB. Our results show that active transmission of MDR- and XDR-TB is taking place and that the high prevalence of observed XDR-TB is due to the continued transmission of particular genetic clusters. Enforcement of the implementation of genotyping in diagnostic routines would lead to early detection of resistant cases. [ABSTRACT FROM AUTHOR]

Objectives: Extensively drug-resistant (XDR) tuberculosis (TB) threatens the global control of TB worldwide. Lisbon has a high XDR-TB rate [50% of the multidrug-resistant tuberculosis (MDR-TB)], which is mainly associated with Lisboa family strains. Few studies have addressed the identification of mutations associated with resistance to second-line injectable drugs, and the relative frequency of such mutations varies geographically. The aim of this study was to characterize the genetic changes associated with the high number of XDR-TB cases in Lisbon. [ABSTRACT FROM PUBLISHER]