Dataset Information

Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds.

ABSTRACT: Acinetobacter baumannii (A. baumannii) is an opportunistic bacterium that has developed multidrug resistance (MDR) to most of today's antibiotics, posing a significant risk to human health. Considering the fact that developing novel drugs is a time-consuming and expensive procedure, this research focuses on utilizing computational resources for repurposing antibacterial agents for A. baumannii. We targeted shikimate kinase, an essential enzyme in A. baumannii, that plays a significant role in the metabolic process. The basis for generating new therapeutic compounds is to inhibit the shikimate kinase and thereby targeting the shikimate pathway. Herein, 1941 drug-like compounds were investigated in different in silico techniques for assessing drug-likeness properties, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, binding affinity, and conformation analysis utilizing Autodock-vina and SwissDock. CHEMBL1237, CHEMBL1237119, CHEMBL2018096, and CHEMBL39167178 were determined as potential drug candidates for suppressing shikimate kinase protein. Molecular Dynamics Simulation (MDS) results for root mean square deviation, root mean square fluctuation, hydrogen bond, and gyration radius confirm the drug candidates' molecular stability with the target protein. According to this study, CHEMBL1237 (Lisinopril) could be the most suitable candidate for A. baumannii. Our investigation suggests that the inhibitors of shikimate kinase could represent promising treatment options for A. baumannii. However, further in vitro and in vivo studies are necessary to validate the therapeutic potential of the suggested drug candidates.

SUBMITTER: Shil A

PROVIDER: S-EPMC10076115 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds.

Shil Aparna A Akter Most Afrin MA Sultana Arafin A Halder Sajal Kumar SK Himel Mahbubul Kabir MK

Journal of tropical medicine 20230329

Acinetobacter baumannii (A. baumannii) is an opportunistic bacterium that has developed multidrug resistance (MDR) to most of today's antibiotics, posing a significant risk to human health. Considering the fact that developing novel drugs is a time-consuming and expensive procedure, this research focuses on utilizing computational resources for repurposing antibacterial agents for A. baumannii. We targeted shikimate kinase, an essential enzyme in A. baumannii, that pl ...[more]

PMID: 37034553

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Project description:Multidrug-Resistant (MDR) and Extensively Drug Resistant (XDR) Acinetobacter baumannii (Ab) represent a serious cause of healthcare-associated infections worldwide. Currently, the available treatment options are very restricted and colistin-based therapies are last-line treatments of these infections, even though colistin resistant (COLR) Ab have rarely been isolated yet. In bacteria, small non-coding RNAs (sRNAs) have been implicated in regulatory pathways of different biological functions, however, no knowledge exists about the sRNA role on the biological adaptation in COLR Ab. Our study investigated two Italian XDR isogenic colistin-susceptible/resistant (COLS/R) Ab strain-pairs to discover new sRNA signatures. Comparative sRNA transcriptome (sRNAome) analyses were carried out by Illumina RNA-seq using both a Tru-Seq and a Short Insert library, whilst Ab ATCC 17978 and ACICU Reference Genome assembly, mapping, annotation and statistically significant differential expression (q-value ≤ 0.01) of the raw reads were performed by the Rockhopper tool. A computational filtering, sorting only similarly statistically significant differentially expressed (DE) sRNAs mapping on the same gene in both COLR Ab isolates was conducted. COLR vs. COLS sRNAome, analyzed integrating the DE sRNAs obtained from the two different libraries, revealed some statistically significant DE sRNAs in COLR Ab. In detail, we found: (i) two different under-expressed cis-acting sRNAs (AbsRNA1 and AbsRNA2) mapping in antisense orientation the 16S rRNA gene A1S_r01, (ii) one under-expressed cis-acting sRNA (AbsRNA3) targeting the A1S_2505 gene (hypothetical protein), (iii) one under-expressed microRNA-size small RNA fragment (AbsRNA4) and its pre-microAbsRNA4 targeting the A1S_0501 gene (hypothetical protein), (iv) as well as an over-expressed microRNA-size small RNA fragment (AbsRNA5) and its pre-microAbsRNA5 targeting the A1S_3097 gene (signal peptide). Custom TaqMan® probe-based real-time qPCRs validated the expression pattern of the selected sRNA candidates shown by RNA-seq. Furthermore, analysis on sRNA ΔA1S_r01, ΔA1S_2505 as well as the over-expressed A1S_3097 mutants revealed no effects on colistin resistance. Our study, for the first time, found the sRNAome signatures of clinical COLR Ab with a computational prediction of their targets related to protein synthesis, host-microbe interaction and other different biological functions, including biofilm production, cell-cycle control, virulence, and antibiotic-resistance.

Dataset Information

Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds.

Publications

Targeting Shikimate Kinase Pathway of <i>Acinetobacter baumannii</i>: A Structure-Based Computational Approach to Identify Antibacterial Compounds.

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