An integrative, multi-omics approach towards the prioritization of Klebsiella pneumoniae drug targets

Abstract

Klebsiella pneumoniae (Kp) is a globally disseminated opportunistic pathogen that can cause life-threatening infections. It has been found as the culprit of many infection outbreaks in hospital environments, being particularly aggressive towards newborns and adults under intensive care. Many Kp strains produce extended-spectrum β-lactamases, enzymes that promote resistance against antibiotics used to fight these infections. The presence of other resistance determinants leading to multidrug-resistance also limit therapeutic options, and the use of ‘last-resort’ drugs, such as polymyxins, is not uncommon. The global emergence and spread of resistant strains underline the need for novel antimicrobials against Kp and related bacterial pathogens. To tackle this great challenge, we generated multiple layers of ‘omics’ data related to Kp and prioritized proteins that could serve as attractive targets for antimicrobial development. Genomics, transcriptomics, structuromic and metabolic information were integrated in order to prioritize candidate targets, and this data compendium is freely available as a web server. Twenty-nine proteins with desirable characteristics from a drug development perspective were shortlisted, which participate in important processes such as lipid synthesis, cofactor production, and core metabolism. Collectively, our results point towards novel targets for the control of Kp and related bacterial pathogens.

Network-Based Metabolism-Centered Screening of Potential Drug Targets in Klebsiella pneumoniae at Genome Scale

“…They are responsible for the biosynthesis of the bacterial cell wall components as described before (Figure 4). Of these five targets, LpxA and LpxC were also suggested as putative drug targets by Ramos et al (2016Ramos et al ( , 2018 confirming the involvement of these enzymes in polymyxin B resistance. The LpxA exhibits no significant structural or sequence homology with mammalian enzymes (Barb and Zhou, 2008;Joo, 2015).…”

“…In-depth examination of the prioritized list of the drug targets reveals a total of 57 non-homologous genes that satisfy at least one prioritization criteria. In a recent multi-omics study by Ramos and colleagues, 29 potential drug targets for MDR K. pneumoniae Kp13 were proposed (Ramos et al, 2018). Comparison of the computational predictions revealed 18 common targets with that study.…”

“…To date, this approach has been commonly used in drug target discovery process at systems-level for different pathogens (Raman et al, 2008;Plata et al, 2010;Perumal et al, 2011;Ahn et al, 2014;Larocque et al, 2014;Presta et al, 2017). GMN models are available for different K. pneumoniae strains (Liao et al, 2011;Henry et al, 2017;Ramos et al, 2018;Norsigian et al, 2019). The first K. pneumoniae model at the genome level, called iYL1228, appeared in 2011 for the MGH 78578 strain (Liao et al, 2011).…”

“…Both works lack a GMN-based identification of drug target candidates. In a recent work, a GMN of multi drug resistant (MDR) Kp13 strain was developed (Ramos et al, 2018). The authors did not perform an FBA-like analysis based on the calculation of flux distributions.…”

Chemical-genetic profiling reveals cross-resistance and collateral sensitivity between antimicrobial peptides

“…Similarly, pssA (a phosphatidylserine synthase) appeared in the presence of LL37, a membrane-targeting AMP. Reassuringly, deletion of pssA has been shown to alter membrane properties and increase bacterial sensitivity to membrane-targeting peptides 36 .…”