Structural and Functional Diversity of Resistance-Nodulation-Cell Division Transporters

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Multidrug resistant (MDR) bacteria are a growing global health concern, diminishing the effectiveness of common antibiotics.
• Bacterial resistance-nodulation-cell division (RND) superfamily proteins are crucial in mediating antimicrobial resistance through multidrug efflux and cell wall biogenesis.
• These RND proteins contribute to the development of 'superbugs' resistant to even last-resort antibiotics.

Purpose of the Study:

• To review the RND superfamily of efflux transporters, focusing on the assembly and function of inner membrane pumps.
• To analyze the structures of bacterial inner membrane efflux pumps and their substrate binding/transport mechanisms.
• To provide mechanistic insights for designing novel efflux pump inhibitors.

Main Methods:

• Literature review of RND superfamily efflux transporters.
• Analysis of recently solved structures of bacterial inner membrane efflux pumps.
• Integration of mechanistic insights with simulated docking techniques.

Main Results:

• RND inner membrane pumps are critical for extruding antibiotics and transporting lipid moieties to the outer membrane, ensuring cell stability.
• Bacterial RND proteins can adopt different oligomerization states to perform various functions, including forming MDR pumps and cell wall remodeling machinery.
• Structural analysis reveals how these pumps bind and transport their substrates.

Conclusions:

• Understanding the structure-function relationship of RND efflux pumps is vital for combating bacterial resistance.
• Mechanistic insights into RND pump activity facilitate the design of new inhibitors to treat difficult-to-cure infections.
• Targeting RND pumps offers a promising strategy to overcome multidrug resistance in bacterial pathogens.