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Global Genomic Diversity, Population Structure and Drug Resistance in the Mycobacterium avium complex
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As micobactérias não-tuberculosas (NTM) têm sido cada vez mais reconhecidas como patogénios oportunistas. Dentro deste grupo, o complexo Mycobacterium avium (MAC) é o principal responsável pela maioria das infeções em humanos. Estes organismos apresentam uma grande diversidade genética e padrões de resistência que dificultam o diagnóstico e o tratamento. Neste trabalho, foram analisados 2 916 genomas de M. avium provenientes de 22 países e isolados de hospedeiros humanos, animais, e de fontes ambientais, para investigar filogenia, estrutura populacional e resistência aos antibióticos. Foram identificadas 4 linhagens principais: três compostas apenas por M. avium subsp. hominissuis (MAH) e uma quarta linhagem constituída por M. avium subsp. avium (MAA), M. avium subsp. paratuberculosis (MAP) e MAH. A subespécie MAH demonstrou maior diversidade genética e um pan-genoma aberto, ao contrário de MAA e MAP, que apresentaram perfis mais conservados e clonais. Mutações em rrl (A2058/A2059) e rrs(A1408G), associadas à resistência aos macrólidos e aminoglicosídeos, foram detetadas apenas em isolados MAH provenientes de humanos. Foram observados clusters de transmissão maioritariamente a nível nacional, e foi também desenvolvido um barcode baseado em SNPs para identificação de linhagens. Em paralelo, 46 isolados clínicos de MAC portugueses, recolhidos entre 2009 e 2018, foram sequenciados e comparados com o contexto global. Estes isolados enquadravam-se nas linhagens MAH sem evidências fortes que indicassem transmissão clonal, sugerindo múltiplas aquisições ambientais independentes. Testes de suscetibilidade aos antibióticos mostraram baixa frequência de resistência para a claritromicina e amicacina, em contraste com o linezolida, para o qual se detetaram elevadas taxas de resistência. Para além destes, foram também detetadas concentrações mínimas inibitórias elevadas para a moxifloxacina, rifamicinas e etambutol. Nenhuma destas resistências foi associada à presença de mutações previamente reportadas. Estes resultados evidenciam a diversidade genética do MAC, a estrutura populacional das duas subespécies e os seus padrões variáveis de resistência.
Nontuberculous mycobacteria (NTM) are increasingly recognized as opportunistic pathogens, with the Mycobacterium avium complex (MAC) responsible for most human infections. These organisms display high genetic diversity and resistance patterns that complicate both diagnosis and treatment. A global dataset of 2 916 high-quality M. avium genomes from 22 countries, spanning human, animal, and environmental sources, was analysed to investigate phylogeny, population structure, and resistance. Four major lineages were identified: three composed exclusively of M. avium subsp. hominissuis (MAH) and a fourth containing M. avium subsp. avium (MAA), M. avium subsp. paratuberculosis (MAP) and MAH. MAH exhibited the highest diversity and an open pangenome, while MAP and MAA were more clonal and conserved. Mutations in rrl (A2058/A2059) and rrs(A1408G), linked to macrolide and aminoglycoside resistance, were detected only in human MAH isolates. Transmission clusters were observed mainly at national level, and a SNP-based barcode was developed for rapid lineage assignment. In parallel, 46 Portuguese MAC clinical isolates collected between 2009–2018 were sequenced and placed in the global context. These were distributed across MAH lineages without strong evidence of clonal transmission, suggesting multiple independent acquisitions from the environment. Phenotypic testing showed low resistance to clarithromycin and amikacin but high resistance to linezolid, with elevated MICs also observed for moxifloxacin, rifamycins, and ethambutol. No known resistance-associated mutations accounted for these patterns, indicating alternative mechanisms of reduced susceptibility. Overall, the results highlight the broad genetic diversity of MAC, the population structures of its subspecies, and the variable patterns of resistance observed across isolates.
Nontuberculous mycobacteria (NTM) are increasingly recognized as opportunistic pathogens, with the Mycobacterium avium complex (MAC) responsible for most human infections. These organisms display high genetic diversity and resistance patterns that complicate both diagnosis and treatment. A global dataset of 2 916 high-quality M. avium genomes from 22 countries, spanning human, animal, and environmental sources, was analysed to investigate phylogeny, population structure, and resistance. Four major lineages were identified: three composed exclusively of M. avium subsp. hominissuis (MAH) and a fourth containing M. avium subsp. avium (MAA), M. avium subsp. paratuberculosis (MAP) and MAH. MAH exhibited the highest diversity and an open pangenome, while MAP and MAA were more clonal and conserved. Mutations in rrl (A2058/A2059) and rrs(A1408G), linked to macrolide and aminoglycoside resistance, were detected only in human MAH isolates. Transmission clusters were observed mainly at national level, and a SNP-based barcode was developed for rapid lineage assignment. In parallel, 46 Portuguese MAC clinical isolates collected between 2009–2018 were sequenced and placed in the global context. These were distributed across MAH lineages without strong evidence of clonal transmission, suggesting multiple independent acquisitions from the environment. Phenotypic testing showed low resistance to clarithromycin and amikacin but high resistance to linezolid, with elevated MICs also observed for moxifloxacin, rifamycins, and ethambutol. No known resistance-associated mutations accounted for these patterns, indicating alternative mechanisms of reduced susceptibility. Overall, the results highlight the broad genetic diversity of MAC, the population structures of its subspecies, and the variable patterns of resistance observed across isolates.
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Mycobacterium avium complex (MAC) Population structure Genetic diversity Drug resistance