Computer aided ligand based screening for identification of promising molecules against enzymes involved in peptidoglycan biosynthetic pathway from Acinetobacter baumannii

Amera, Gizachew Muluneh; Khan, Rameez Jabeer; Pathak, Abhishek; Jha, Rajat Kumar; Muthukumaran, Jayaraman; Singh, Amit Kumar

doi:10.1016/j.micpath.2020.104205

Cited by 14 publications

(12 citation statements)

References 39 publications

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“…Since, antigenic sites are crucial for pathogenicity and virulence of the microorganism. In this study, we found 16,22,13,14,21,19,25, and 20 putative antigenic sites for MurB, MurE, MraY, MurG, MurD, MurF, MurC, and MurA, respectively and most of the antigenic sites are found in the binding pocket of concerned protein.…”

Section: Prediction Of Functional Domains Subcellular Localization mentioning

confidence: 55%

“…The final steps of the peptidoglycan pathway, the transfer of a GlcNAc subunit on undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide (lipid intermediate I) to form undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide) GlcNAc (lipid intermediate II) is catalyzed by MurG protein [ 13 ]. All of the enzymes are responsible for the synthesis of peptidoglycan in a sequential manner in bacteria, and this pathway is unique for them and it is not found in human [ 14 ]. So that, the prioritization of the enzymes involved in this pathway as a potential drug target is crucial to counterpart the severity of A .…”

Section: Introductionmentioning

confidence: 99%

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Prioritization of Mur family drug targets against A. baumannii and identification of their homologous proteins through molecular phylogeny, primary sequence, and structural analysis

Amera

Khan

Jha

et al. 2020

Journal of Genetic Engineering and Biotechnology

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Background: The World Health Organization (WHO) report stated that Acinetobacter baumannii had been classified as one of the most important pathogenic bacteria causing nosocomial infection in hospital patients due to multidrug resistance (MDR). It is vital to find out new bacterial drug targets and annotated their structure and function for the exploration of new anti-bacterial agents. The present study utilized a systematic route to prioritize the potential drug targets that belong to Mur family of Acinetobacter baumannii and identify their homologous proteins using a computational approach such as sequence similarity search, multiple sequence alignment, phylogenetic analysis, protein sequence, and protein structure analysis. Results: From the results of protein sequence analysis of eight Mur family proteins, they divided into three main enzymatic classes namely transferases (MurG, MurA and MraY), ligases (MurC, MurD, MurE, and MurF), and oxidoreductase (MurB). Based on the results of intra-comparative protein sequence analysis and enzymatic classification, we have chosen MurB, MurE, and MurG as the prioritized drug targets from A. baumannii and subjected them for further detailed studies of inter-species comparison. This inter-species comparison help us to explore the sequential and structural properties of homologous proteins in other species and hence, opens a gateway for new target identification and using common inhibitor for different bacterial species caused by various diseases. The pairwise sequence alignment results between A. baumannii's MurB with A. calcoaceticus's MurB, A. baumannii's MurE with A. seifertii's MurE, and A. baumannii's MurG with A. pittii's MurG showed that every group of the proteins are highly similar with each other and they showed sequence identity of 95.7% and sequence similarity of 97.2%. Conclusion: Together with the results of secondary and three-dimensional structure predictions explained that three selected proteins (MurB, MurE, and MurG) from A. baumannii and their related proteins (AcMurB, AsMurE, and ApMurG) belong to mixed αβ class and they are very similar.

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Section: Prediction Of Functional Domains Subcellular Localization mentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Prioritization of Mur family drug targets against A. baumannii and identification of their homologous proteins through molecular phylogeny, primary sequence, and structural analysis

Amera

Khan

Jha

et al. 2020

Journal of Genetic Engineering and Biotechnology

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“…28 Similarly, Ramachandran et al conducted molecular docking and free energy calculations to understand the drug interactions with oxacillinases produced by A. baumannii. [29][30][31] The presence of proteases (serine protease, lysosomal acid alpha-glucosidase, cysteine protease, human calpain-1, prolylcarboxypeptidase, thimet oligopeptidase, dipeptidyl peptidase) lowers the stability of AMPs in biological fluids. This impedes the therapeutic application of AMPs in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Novel Mastoparan-Chitosan Nanoconstructs Against Clinical MDR Acinetobacter baumannii: In silico, in vitro and in vivo Studies

Hassan

Ikram

Raza

et al. 2021

IJN

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Purpose Acinetobacter baumannii antibiotic resistant infections in high-risk patients are a great challenge for researchers and clinicians worldwide. In an effort to achieve potent bactericidal outcomes, a novel chitosan–mastoparan nanoconstruct (Mast-Cs NC) was designed and assessed for its therapeutic potential through in silico, in vitro and in vivo experimentation against clinical multidrug-resistant (MDR) A. baumannii . Methods Optimized 3D structures of mastoparan and chitosan were coupled computationally through an ionic cross-linker to generate a circular ring of chitosan encasing mastoparan. The complex was assessed for interactions and stability through molecular dynamic simulation (MDS). Binding pocket analysis was used to assess the protease–peptide interface. Mast-Cs NC were prepared by the ionic gelation method. Mast-Cs NC were evaluated in vitro and in vivo for their therapeutic efficacy against drug-resistant clinical A. baumannii . Results MDS for 100 ns showed stable bonds between chitosan and mastoparan; the first at chitosan oxygen atom-46 and mastoparan isoleucine carbon atom with a distance of 2.77 Å, and the second between oxygen atom-23 and mastoparan lysine nitrogen atom with a distance of 2.80 Å, and binding energies of −3.6 and −7.4 kcal/mol, respectively. Mast-Cs complexes approximately 156 nm in size, with +54.9 mV zeta potential and 22.63% loading capacity, offered >90% encapsulation efficiency and were found to be geometrically incompatible with binding pockets of various proteases. The MIC 90 of Mast-Cs NC was significantly lower than that of chitosan (4 vs 512 μg/mL, respectively, p <0.05), with noticeable bacterial damage upon morphological analysis. In a BALB/c mouse sepsis model, a significant reduction in bacterial colony count in the Mast-Cs treated group was observed compared with chitosan and mastoparan alone ( p <0.005). Mast-Cs maintained good biocompatibility and cytocompatibility. Conclusion Novel mastoparan-loaded chitosan nanoconstructs signify a successful strategy for achieving a synergistic bactericidal effect and higher therapeutic efficacy against MDR clinical A. baumannii isolates. The Mast-Cs nano-drug delivery system could work as an alternative promising treatment option against MDR A. baumannii .

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“…Zeta Toxin‐Epsilon Antitoxin was initially identified in Streptococcus pneumonia and later in Streptococcus pyogenes , Staphylococcus aureus , Enterococcus faecalis , Clostridium perfringens , Neisseria gonorrhoeae , Acinetobacter johnsonii , etc 17–20 . Based on the interaction profile, the TA systems were generally classified into eight different types 21,22 . The Toxin exists in the form of protein, whereas the Antitoxin may be either in the form of RNA or protein.…”

Section: Introductionmentioning

confidence: 99%

“…Upon activation, Zeta Toxin phosphorylates the ubiquitous peptidoglycan precursor uridine diphosphate‐ N ‐acetylglucosamine (UNAG) with the aid of UNAG kinase and forms UDP‐ N ‐acetylglucosamine‐3′‐phosphate (UNAG‐3P). The phosphorylation reaction is catalyzed by UNAG kinase in the presence of ATP as cofactor 2,15,18–21 . The UNAG kinase facilitates the transfer of the phosphate group from ATP to the ‐OH group (C3′) of UNAG, which prevents the peptidoglycan biosynthesis (Figure 1C).…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation of Toxin‐Antitoxin (TA) system in Acinetobacter baumannii to explore the novel mechanism for inhibition of cell wall biosynthesis: Zeta Toxin as an effective therapeutic target

Karthika

Ramachandran

Jeyarajpandian³

et al. 2021

J of Cellular Biochemistry

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The majority of bacteria and archaea contains Toxin‐Antitoxin system (TA) that codes for the stable Toxin and unstable Antitoxin components forming a complex. The Antitoxin inhibits the catalytic activities of the Toxin. In general, the Antitoxin will be degraded by the proteases leading to the Toxin activation that subsequently targets essential cellular processes, including transcription, translation, replication, cell division, and cell wall biosynthesis. The Zeta Toxin‐Epsilon Antitoxin system in ESKAPE pathogen stabilizes the resistance plasmid and promotes pathogenicity. The known TA system in Acinetobacter baumannii are known to be involved in the replication and translation, however, the mechanism of Zeta Toxin‐Epsilon Antitoxin in cell wall biosynthesis remains unknown. In the present study, molecular docking and molecular dynamic (MD) simulations were employed to demonstrate whether Zeta Toxin can impair cell wall synthesis in A. baumannii. Further, the degradation mechanism of Antitoxin in the presence and absence of adenosine triphosphate (ATP) molecules are explained through MD simulation. The result reveals that the cleavage of Antitoxin could be possible with the presence of ATP by displaying its response from 20 ns, whereas the Zeta Toxin/Epsilon was unstable after 90 ns. The obtained results demonstrate that Zeta Toxin is “temporarily favorable” for ATP to undergo phosphorylation at UNAG kinase through the substrate tunneling process. The study further evidenced that phosphorylated UNAG prevents the binding of MurA, the enzyme that catalyzes the initial step of bacterial peptidoglycan biosynthesis. Therefore, the present study explores the binding mechanism of Zeta Toxin/Epsilon Antitoxin, which could be beneficial for preventing cell wall biosynthesis as well as for unveiling the alternative treatment options to antibiotics.

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Computer aided ligand based screening for identification of promising molecules against enzymes involved in peptidoglycan biosynthetic pathway from Acinetobacter baumannii

Cited by 14 publications

References 39 publications

Prioritization of Mur family drug targets against A. baumannii and identification of their homologous proteins through molecular phylogeny, primary sequence, and structural analysis

Prioritization of Mur family drug targets against A. baumannii and identification of their homologous proteins through molecular phylogeny, primary sequence, and structural analysis

Therapeutic Potential of Novel Mastoparan-Chitosan Nanoconstructs Against Clinical MDR Acinetobacter baumannii: In silico, in vitro and in vivo Studies

Molecular dynamics simulation of Toxin‐Antitoxin (TA) system in Acinetobacter baumannii to explore the novel mechanism for inhibition of cell wall biosynthesis: Zeta Toxin as an effective therapeutic target

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