Impairment of two non-essential LytR-cpsA-psr (Lcp) cell wall ligases decelerate cell wall assembly in Mycolicibacterium smegmatis

The LytR-CpsA-Psr (Lcp) family of proteins are highly abundant amongst actinomycetes and Gram-positive bacteria, and known to exist as multiple paralogs in an organism. Several reports demonstrated the essential LcpA to play a crucial role in coupling cell wall teichoic acids (arabinogalactan in mycobacteria) to peptidoglycan, making it an attractive drug target against tuberculosis (TB). However, apart from LcpB that accommodates capsular biosynthesis, role of the non-essential Lcp paralogs in mycobacteria largely remains elusive. Therefore, we made a comprehensive approach in characterizing the role of these non-essential Lcp proteins in mycobacterial cell wall assembly. Additionally, we used homology and interactive models as an alternate approach to X-ray crystallography, to identify hotspot residues for Lcp inhibition and subsequent bactericidal activity.