Stress response SigH enables drug resistance in Mycobacterium abscessus

Mycobacterium abscessus (Mab) is a bacterium that causes serious lung infections and is notoriously hard to treat because it resists many antibiotics. Current treatment options are limited, and the mechanisms behind that resistance are complex and not well understood. To look for new ways to fight these infections, Shuai Wang and collaborators focused on a bacterial protein called SigH, known from related bacteria to help cells respond to stress. Mab SigH shares an 84% peptide sequence identity with Mycobacterium tuberculosis (Mtb) SigH, suggesting it could play a similar regulatory role. The team set out to test whether SigH helps Mab survive antibiotic exposure and other stresses. They built a strain in which the sigH gene was deleted (Δ sigH) and then made complemented strains that reintroduced either the native Mab sigH (CPMab sigH) or the Mtb version (CPMtb sigH). By comparing the behavior of the wild-type strain, the Δ sigH deletion strain, and the complemented strains under antibiotic treatment and stressful conditions, the researchers could directly test whether SigH is important for the bacterium’s intrinsic defenses.

The key methods and results center on genetic manipulation and whole-cell tests. The researchers constructed a sigH gene deletion strain (Δ sigH) and two complemented strains expressing either Mab sigH (CPMab sigH) or Mtb sigH (CPMtb sigH) in the Δ sigH background. The Δ sigH strain showed hypersensitivity to a broad set of antibiotics, including levofloxacin, moxifloxacin, tigecycline, tetracycline, amikacin, vancomycin, and rifabutin. Introducing either CPMab sigH or CPMtb sigH restored the drug resistance phenotype, indicating that SigH function is required for intrinsic resistance. Beyond antibiotics, Δ sigH was more sensitive to oxidative and heat stress compared to wild-type Mab and the complemented strains, linking SigH to general stress responses. Transcriptomic analysis revealed that deleting sigH disrupted global gene expression: genes encoding YrbE and MCE family proteins were primarily elevated, while genes expressing ABC-type transporters, sigma and anti-sigma factors and other genes associated with antimicrobial resistance were downregulated. Together, these methods and findings identify SigH as a global regulator affecting many resistance-related pathways.

These findings suggest a clear role for SigH as a central regulator that helps Mab survive both environmental stresses and antibiotic treatment. By controlling large-scale changes in gene expression—boosting some protein families while repressing others—SigH appears to support the bacterium’s intrinsic multi-drug resistance. Because removing sigH makes Mab far more susceptible to a range of antibiotics, SigH represents a promising target for new treatments: drugs or approaches that inhibit SigH could sensitize Mab to existing antibiotics such as levofloxacin, moxifloxacin, tigecycline, tetracycline, amikacin, vancomycin, and rifabutin. The ability of the Mtb SigH to complement the Mab deletion also highlights conserved features that might be exploited across related mycobacteria. Overall, targeting a global stress response regulator like SigH offers a strategic alternative to designing single-antibiotic agents, potentially opening paths to therapies that overcome the bacterium’s intrinsic defenses and improve outcomes for patients with Mab pulmonary disease.