Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets

Abstract

Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex known as a divisome. Central to the divisome are the proteins FtsB and FtsL binding to FtsQ to form a complex FtsQBL, which helps link the early proteins with late proteins. The FtsQBL complex is highly conserved as a component across bacteria. Pathogens like Vibrio cholerae, Mycobacterium ulcerans, Mycobacterium leprae, and Chlamydia trachomatis are the causative agents of the bacterial Neglected Tropical Diseases Cholera, Buruli ulcer, Leprosy, and Trachoma, respectively, some of which seemingly lack known homologs for some of the FtsQBL complex proteins. In the absence of experimental characterization, either due to insufficient resources or the massive increase in novel sequences generated from genomics, functional annotation is traditionally inferred by sequence similarity to a known homolog. With the advent of accurate protein structure prediction methods, features both at the fold level and at the protein interaction level can be used to identify orthologs that cannot be unambiguously identified using sequence similarity methods. Using the FtsQBL complex proteins as a case study, we report potential remote homologs using Profile Hidden Markov models and structures predicted using AlphaFold. Predicted ortholog structures show conformational similarity with corresponding E. coli proteins irrespective of their level of sequence similarity. Alphafold multimer was used to characterize remote homologs as FtsB or FtsL, when they were not sufficiently distinguishable at both the sequence or structure level, as their interactions with FtsQ and FtsW play a crucial role in their function. The structures were then analyzed to identify functionally critical regions of the proteins consistent with their homologs and delineate regions potentially useful for inhibitor discovery.

The essential domain of FtsN triggers cell division by promoting interaction between FtsL and FtsI

“…Besides contacting L89 of E FtsN, Y85 of E FtsN is also packed against Y168 of FtsI. Interestingly, FtsN cannot be identified in Gram positive organisms and the AWI FtsL domain is not well conserved among Gram positive bacteria suggesting some variation on the activation mechanism is likely in these bacteria 33 .…”

Revolutionizing Medicinal Chemistry: The Application of Artificial Intelligence (AI) in Early Drug Discovery

“…Lastly, HMMs are instrumental in predicting protein structures and 3D modeling. Accurately predicting and modeling complex protein structures is a crucial part of drug discovery, as it assists in predicting the efficacy and binding characteristics of a potential drug [ 45 ].…”

Amber‐codon suppression for spatial localization and in vivo photoaffinity capture of the interactome of the Pseudomonas aeruginosa rare lipoprotein A lytic transglycosylase

“…Biosynthesis and turnover of the peptidoglycan is dynamic. In rod‐shaped bacteria such as P. aeruginosa , peptidoglycan synthesis is catalyzed by two separate multiprotein/multienzyme complexes: the elongasome and the divisome (Attaibi & den Blaauwen, 2022; Egan et al, 2017; Kaur & Lynn, 2022; Kohyama et al, 2022; Rohs et al, 2021; van der Ploeg et al, 2013). The former lengthens the bacterium along its rod sidewalls, and the latter synthesizes a mid‐cell septum, which when complete, is cleaved to dissociate the daughter cells.…”