PE/PPE proteins contribute to Mycobacterium tuberculosis drug resistance

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• The mycobacterial outer membrane (OM) presents a significant barrier to antibiotic entry.
• The role of PE (proline-glutamic acid) and PPE (proline-proline-glutamic acid) proteins, potential OM transporters, in drug resistance is largely unexplored.
• Bacterial transporters are known contributors to antimicrobial resistance.

Purpose of the Study:

• To investigate the role of PE/PPE proteins in Mycobacterium tuberculosis (Mtb) drug susceptibility and resistance.
• To determine if PE/PPE proteins contribute to clinical drug resistance phenotypes.

Main Methods:

• Genetic association study to identify mutations in pe/ppe genes linked to drug resistance.
• In vitro drug susceptibility testing of Mtb strains with specific pe/ppe gene mutations or deletions.
• Analysis of gene expression changes, including inner membrane efflux pumps, following pe/ppe gene manipulation.

Main Results:

• Mutations in multiple pe/ppe genes were strongly associated with Mtb drug resistance.
• A specific mutation in ppe42 correlated with clinical amikacin resistance and conferred increased resistance in vitro.
• Deletion of ppe51 resulted in resistance to multiple drugs and upregulation of efflux pumps.
• Deletion of the pe25/ppe41 gene pair increased resistance to isoniazid (INH) and accelerated INH resistance emergence.

Conclusions:

• Several Mtb PE/PPE proteins function as transporters involved in drug resistance, supporting the PE/PPE transporter paradigm.
• The PE/PPE protein family plays a broader role in Mtb drug susceptibility and clinical drug resistance.
• Targeting PE/PPE proteins may offer novel strategies to overcome Mtb drug resistance.