Multi-clonal evolution of MDR/XDRM. tuberculosisin a high prevalence setting in Papua New Guinea over three decades

An outbreak of multi-drug resistant tuberculosis has been reported on Daru Island, Papua New Guinea. The Mycobacterium tuberculosis strains driving this outbreak and the temporal accrual of drug resistance mutations have not been described. We analyzed 100 isolates using whole genome sequencing and found 95 belonged to a single modern Beijing strain cluster. Molecular dating suggested acquisition of streptomycin and isoniazid resistance in the 1960s, with virulence potentially enhanced by a mycP1 mutation. The outbreak cluster demonstrated a high degree of co-resistance between isoniazid and ethionamide (80/95; 84.2%) attributed to an inhA promoter mutation combined with inhA and ndh coding mutations. Multidrug resistance (MDR), observed in 78/95 samples, emerged with the acquisition of a typical rpoB mutation together with a compensatory rpoC mutation in the 1980s. There was independent acquisition of fluoroquinolone and aminoglycoside resistance; with evidence of local transmission of extensively-drug resistant (XDR) strains from 2009. These findings underscore the importance of whole-genome sequencing in informing an effective public health response to MDR/XDR M. tuberculosis.