Development of antibacterial compounds that constrain evolutionary pathways to resistance

Zhang, Yanmin; Chowdhury, Sourav; Rodrigues, João V.; Shakhnovich, E. I.

doi:10.7554/elife.64518

Cited by 15 publications

(23 citation statements)

References 96 publications

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“…UMP, a constituent of pyrimidine metabolism also showed cellular build up with 32-fold higher abundance after 12 hours of growth with treatment. Also, significant fold differences in the abundance levels of various peptides, cofactors and lipids were observed which too could be attributed to a CD15-3 induced metabolic stress response (Zhang et al, 2021). We observed significant fold differences in some metabolites constituting carbohydrate metabolism.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, wild type cells were grown in the presence of the externally supplemented metabolites under conditions of CD15-3 treatment. These externally supplemented metabolites were selected owing to their highly perturbed abundance levels in the comparative global metabolome (CD15-3 treated versus untreated) and their proximity to folate pathway, as DHFR was the intended target for CD15-3 (Zhang et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

“…We deployed this workflow to identify the functional target of CD15-3, a novel antibiotic compound previously developed in house (Zhang et al, 2021). CD15-3 was designed to interact with wild type DHFR (dihydrofolate reductase) and its trimethoprim (TMP) resistant mutants (Zhang et al, 2021). In our previous report we showed that CD15-3 interacts with DHFR; however, overexpression of the DHFR-encoding gene folA was only able to partially rescue CD15-3-induced growth inhibition.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous report we showed that CD15-3 interacts with DHFR; however, overexpression of the DHFR-encoding gene folA was only able to partially rescue CD15-3-induced growth inhibition. The lack of complete growth rescue from overexpression of DHFR indicated the presence of an additional non-DHFR intracellular target of CD15-3, which could be responsible for the growth inhibitory effect of the compound (Rodrigues and Shakhnovich, 2019a; Zhang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Empowering systems-guided drug target discovery with metabolic and structural analysis

Chowdhury

Dalldorf

et al. 2021

Preprint

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Understanding intracellular antibiotic targeting and the associated mechanisms leading to bacterial growth inhibition has been a difficult problem. Here, we discovered the additional intracellular targets of the novelevolution-drug lead CD15-3 designed to delay the emergence of antibiotic resistance by inhibiting bacterial DHFR and its Trimethoprim resistant variants. Overexpression of DHFR only partially rescued inhibition of E. coli growth by CD15.3 suggesting that CD15.3 also inhibits a non-DHFR target in the cell. We utilized untargeted global metabolomics and the metabolic network analysis along with structural similarity search of the putative targets to identify the additional target of CD15-3. We validated in vivo and in vitro that besides DHFR CD15-3 inhibits HPPK (folK), an essential protein upstream of DHFR in bacterial folate metabolism. This bivalent cellular targeting makes CD15-3 a promising lead to develop a monotherapy analogue of combination drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Empowering systems-guided drug target discovery with metabolic and structural analysis

Chowdhury

Dalldorf

et al. 2021

Preprint

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“…Dihydrofolate reductase telah menarik banyak perhatian sebagai target molekuler, dimana dihydrofolate reductase merupakan suatu enzim yang mengkatalisis reduksi yang bergantung pada nikotinamida adeninukleotida fosfat (NADPH) dari dihidrofolat menjadi tetrahidrofolat (7,8-DHF menjadi 5,6,7,8-THF) dalam sel mikroba dan eukariota (Wróbel et al, 2020). Dihydrofolate reductase adalah salah satu protein yang karena perannya yang penting dalam biosintesis nukleotida, telah menjadi target obat antibakteri (Zhang et al, 2021;Aragaw et al, 2021;Dias et al, 2014).…”

Section: Pendahuluanunclassified

Studi In Silico Kandungan Senyawa Daun Srikaya (Annona squamosa L.)Terhadap Protein Dihydrofolate Reductase Pada Mycobacterium tuberculosis

Endriyatno

Walid

2022

Pharmacon

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Tuberculosis is caused by the Mycobacterium tuberculosis. Tuberculosis is one of the problems in the world, especially the problem of resistance which requires the search for new alternative drugs, one of which is from natural compounds.In silico studies with molecular docking method can be used as a preliminary test to assess the potency of a natural compound. In this study, the target proteins were Dihydrofolate Reductase: 4KL9 and 4KM2 with the original P33 and ATR ligands on Mycobacterium tuberculosis. Dihydrofolate reductase is a protein that has an important role in nucleotide biosynthesis, and has become a target for antibacterial drugs. The natural compounds tested were anonaine, asimilobine, and corypalmine contained in soursop leaves. The molecular docking results showed that the three compounds had docking score, especially for the 4KL9 target protein, which was lower than the original ligand. A lower value means that the binding of the ligand and target protein is stronger than that of the native ligand. The three compound ligands on the target protein 4KM2 have a higher docking score than the original ligand, meaning that the binding of the three ligands is not as strong as the original ligand, but the values are not far apart. In addition, there are similar residues involved from the original ligand and the ligands of the three compounds to the target protein. Therefore, it can be concluded based on an in silico study of the content of anonaine, asimilobine, and corypalmine compounds that may have antituberculosis activity.

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DHFR Mutants Modulate Their Synchronized Dynamics with the Substrate by Shifting Hydrogen Bond Occupancies

Cetin

Atılgan

2022

J. Chem. Inf. Model.

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Antibiotic resistance is a global health problem in which mutations occurring in functional proteins render drugs ineffective. The working mechanisms of the arising mutants are seldom apparent; a methodology to decipher these mechanisms systematically would render devising therapies to control the arising mutational pathways possible. Here we utilize Cα–Cβ bond vector relaxations obtained from moderate length MD trajectories to determine conduits for functionality of the resistance conferring mutants of Escherichia coli dihydrofolate reductase. We find that the whole enzyme is synchronized to the motions of the substrate, irrespective of the mutation introducing gain-of-function or loss-of function. The total coordination of the motions suggests changes in the hydrogen bond dynamics with respect to the wild type as a possible route to determine and classify the mode-of-action of individual mutants. As a result, nine trimethoprim-resistant point mutations arising frequently in evolution experiments are categorized. One group of mutants that display the largest occurrence (L28R, W30G) work directly by modifying the dihydrofolate binding region. Conversely, W30R works indirectly by the formation of the E139–R30 salt bridge which releases energy resulting from tight binding by distorting the binding cavity. A third group (D27E, F153S, I94L) arising as single, resistance invoking mutants in evolution experiment trajectories allosterically and dynamically affects a hydrogen bonding motif formed at residues 59–69–71 which in turn modifies the binding site dynamics. The final group (I5F, A26T, R98P) consists of those mutants that have properties most similar to the wild type; these only appear after one of the other mutants is fixed on the protein structure and therefore display clear epistasis. Thus, we show that the binding event is governed by the entire enzyme dynamics while the binding site residues play gating roles. The adjustments made in the total enzyme in response to point mutations are what make quantifying and pinpointing their effect a hard problem. Here, we show that hydrogen bond dynamics recorded on sub-μs time scales provide the necessary fingerprints to decipher the various mechanisms at play.

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Development of antibacterial compounds that constrain evolutionary pathways to resistance

Cited by 15 publications

References 96 publications

Empowering systems-guided drug target discovery with metabolic and structural analysis

Empowering systems-guided drug target discovery with metabolic and structural analysis

Studi In Silico Kandungan Senyawa Daun Srikaya (Annona squamosa L.)Terhadap Protein Dihydrofolate Reductase Pada Mycobacterium tuberculosis

DHFR Mutants Modulate Their Synchronized Dynamics with the Substrate by Shifting Hydrogen Bond Occupancies

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