Abstract:
Antimicrobial-resistant (AMR) infections pose a major threat to
global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are
characterized by transmission of a limited number of predominant
Mycobacterium tuberculosis (Mtb) strains. Understanding how
these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or
public health surveillance, can inform strategies for prevention and
containment. In this study, we employ whole-genome sequence
(WGS) data from TB clinical isolates collected in KwaZulu-Natal,
South Africa to examine the pre-detection history of a successful
strain of extensively drug-resistant (XDR) TB known as LAM4/KZN,
first identified in a widely reported cluster of cases in 2005. We
identify marked expansion of this strain concurrent with the onset
of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km
away from the site of the 2005 outbreak, and use protein structural
modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in
LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration,
and pathoadaptive evolution in the emergence and dispersal of this
critical public health threat. We propose that integrating wholegenome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens
before they achieve widespread dispersal.
