Structure of Mycobacterium smegmatis Eis in complex with paromomycin

Area of Science:

• Microbiology
• Structural Biology
• Drug Discovery

Background:

• The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Mtb) is crucial for pathogen survival within host macrophages and contributes to aminoglycoside antibiotic resistance.
• Mtb Eis modulates host immune responses and shares structural similarity with the homologous protein in nonpathogenic M. smegmatis (Msm).

Purpose of the Study:

• To elucidate the structural basis of aminoglycoside binding and acetylation by Msm Eis.
• To provide insights for the structure-guided development of novel antituberculosis agents targeting Eis.

Main Methods:

• Crystallization of M. smegmatis Eis (Msm Eis) in complex with the aminoglycoside antibiotic paromomycin.
• Determination of the Msm Eis-paromomycin complex structure at 3.3 Å resolution.

Main Results:

• The crystal structure reveals detailed molecular interactions between Msm Eis and paromomycin.
• Both Mtb Eis and Msm Eis exhibit aminoglycoside acetyltransferase activity.
• Only Mtb Eis possesses N(ℇ)-acetyltransferase activity, suppressing host immune responses via DUSP16/MKP-7 acetylation.

Conclusions:

• The determined structure of Msm Eis provides a valuable template for understanding aminoglycoside interactions.
• This structural information can guide the design of inhibitors targeting Eis for combating drug-resistant tuberculosis.