Archives: Publication

Published in: eBioMedicine

Volume 102, April 2024, 105073

Authors: Benjamin Blasco, Soojin Jang, Hiroki Terauchi, Naoki Kobayashi, Shuichi Suzuki, Yuichiro Akao, Atsuko Ochida, Nao Morishita, Terufumi Takagi, Hiroyuki Nagamiya, Yamato Suzuki, Toshiaki Watanabe, Hyunjung Lee, Sol Lee, David Shum, Ahreum Cho, Dahae Koh, Soonju Park, Honggun Lee, Kideok Kim, Henni-Karoliina Ropponen, Renata Maria Augusto da Costa, Steven Dunn, Sunil Ghosh(TCGLS MEMBER), Peter Sjö, Laura J.V. Piddock

Abstract: The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections. METHODS: We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K. pneumoniae and A. baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using “eNTRy rules” criteria associated with increased likelihood of intracellular accumulation in Escherichia coli. FINDINGS: We identified 72 compounds with confirmed activity against K. pneumoniae and/or drug-resistant A. baumannii. Two new chemical series with activity against XDR A. baumannii were identified meeting our criteria of potency (EC₅₀ ≤50 μM) and absence of cytotoxicity (HepG2 CC₅₀ ≥100 μM and red blood cell lysis HC₅₀ ≥100 μM). The activity of close analogues of the two chemical series was also determined against A. baumannii clinical isolates. INTERPRETATION: This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K. pneumoniae and A. baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects. FUNDING: BMBF and GARDP.

Published in: Nat Commun 15, 937 (2024).

DOI: 10.21203/rs.3.rs-3198291/v1

Authors: Stanley C. Xie, Yinuo Wang, Craig J. Morton, Riley D. Metcalfe, Con Dogovski, Charisse Flerida A. Pasaje, Elyse Dunn, Madeline R. Luth, KrittikornKumpornsin, Eva S. Istvan, Joon Sung Park, Kate J. Fairhurst, NutpakalKetprasit, Tomas Yeo, Okan Yildirim, Mathamsanqa N. Bhebhe, Dana M. Klug, Peter J. Rutledge, Luiz C. Godoy, Sumanta Dey, Mariana Laureano De Souza, Jair L. Siqueira-Neto, Yawei Du, Tanya Puhalovich, Mona Amini, Gerry Shami, DuangkamonLoesbanluechai, Shuai Nie, Nicholas Williamson, Gouranga P. Jana(TCGLS MEMBER), Bikash C. Maity(TCGLS MEMBER), Patrick Thomson, Thomas Foley, Derek S. Tan, Jacquin C. Niles, Byung Woo Han, Daniel E. Goldberg, Jeremy Burrows, David A. Fidock, Marcus C. S. Lee, Elizabeth A. Winzeler, Michael D. W. Griffin, Matthew H. Todd & Leann Tilley.

Abstract: Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Published in: SCIENCE, 23 Nov 2023, Vol 382, Issue 6673, pp. 935-940

Authors: GANESH M. NAWKAR, MARTINA, ANUPAMA GOYAL (TCGLS MEMBER), EMANUEL SCHMID-SIEGERT, JÉRÉMY FLEURY, ANTONIO MUCCIOLO, DAMIEN DE BELLIS, MARTINE TREVISAN, ANDREAS, AND CHRISTIAN FANKHAUSER

DOI: https://www.science.org/doi/10.1126/science.adh9384

Abstract: In plants, light direction is perceived by the phototropin photoreceptors, which trigger directional growth responses known as phototropism. The formation of a phototropin activation gradient across a photosensitive organ initiates this response. However, the optical tissue properties that functionally contribute to phototropism remain unclear. In this work, we show that intercellular air channels limit light transmittance through various organs in several species. Air channels enhance light scattering in Arabidopsis hypocotyls, thereby steepening the light gradient. This is required for an efficient phototropic response in Arabidopsis and Brassica. We identified an embryonically expressed ABC transporter required for the presence of air channels in seedlings and a structure surrounding them. Our work provides insights into intercellular air space development or maintenance and identifies a mechanism of directional light sensing in plants.

Published in: J. Org. Chem

DOI: 10.1021/acs.joc.3c01852

Authors: Arun Kumar Hajra(TCGLS Member), Prasanjit Ghosh*, Priyanka Paul(TCGLS Member), Mrinalkanti Kundu*(TCGLS Member), and Sajal Das*

Abstract: An operationally simple and efficient protocol for copper(II)-mediated, picolinamido-directed C8–H sulfonamidation of 1-naphthylamine derivatives with various sulfonamides has been developed. Remarkably, this cross-dehydrogenative C–H/H–N coupling reaction exhibits a broad substrate scope with excellent functional group tolerance, is scalable, and enables an expeditious route to a library of unsymmetrical N-arylated sulfonamides in good to excellent yields with exclusive site selectivity.

Published in: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.3c00369

Authors: Nicolas Bosc, Eloy Felix, J. Mark F. Gardner, James Mills, Martijn Timmerman, Dennis Asveld,Kim Rensen, Partha Mukherjee(TCGLS Member), Rishi Das(TCGLS Member), Elodie Chenu, Dominique Besson, Jeremy N. Burrows,James Duffy, Benoît Laleu, Eric M. Guantai, and Andrew R. Leach

Abstract: Efforts to tackle malaria must continue for a disease that threatens half of the global population. Parasite resistance to current therapies requires new chemotypes that are able to demonstrate effectiveness and safety. Previously, we developed a machine-learning-based approach to predict compound antimalarial activity, which was trained on the compound collections of several organizations. The resulting prediction platform, MAIP, was made freely available to the scientific community and offers a solution to prioritize molecules of interest in virtual screening and hit-to-lead optimization. Here, we experimentally validate MAIP and demonstrate how the approach was used in combination with a robust compound selection workflow and a recently introduced innovative high-throughput screening (HTS) cascade to select and purchase compounds from a public library for subsequent experimental screening. We observed a 12-fold enrichment compared with a randomly selected set of molecules, and the eight hits we ultimately selected exhibit good potency and absorption, distribution, metabolism, and excretion (ADME) profiles.

Published in: Research square Journal; Preprint 2023

DOI: 10.21203/rs.3.rs-3198291/v1

Authors: Xie, Stanley C ; Wang, Yinuo; Morton, Craig J ; Metcalfe, Riley D; Dogovski, Con; Pasaje, Charisse Flerida A ; Dunn, Elyse; Luth, Madeline R; Kumpornsin, Krittikorn; Istvan, Eva S ; Park, Joon Sung ; Fairhurst, Kate J; Ketprasit, Nutpakal ; Yeo, Tomas ; Yildirim, Okan; Bhebhe, Mathamsanqa N; Klug, Dana M; Rutledge, Peter J ; Godoy, Luiz C; Dey, Sumanta; De Souza, Mariana Laureano; Siqueira-Neto, Jair L; Du, Yawei; Puhalovich, Tanya; Amini, Mona; Shami, Gerry ; Loesbanluechai, Duangkamon; Nie, Shuai; Williamson, Nicholas ; Jana, Gouranga P (TCGLS Member); Maity, Bikash C (TCGLS Member); Thomson, Patrick ; Foley, Thomas; Tan, Derek S ; Niles, Jacquin C ; Han, Byung Woo ; Goldberg, Daniel E ; Burrows, Jeremy ; Fidock, David A ; Lee, Marcus C S; Winzeler, Elizabeth A; Griffin, Michael D W ; Todd, Matthew H ; Tilley, Leann

Abstract: Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

Published in: Journal,

DOI : 10.1021/acs.oprd.3c00287

Author : Robey, Juliana M. S.; Maity, Sanjay; Aleshire, Sarah L.; Ghosh, Angshuman; Yadaw, Ajay K.; Roy, Subho; Mear, Sarah Jane; Jamison, Timothy F.; Sirasani, Gopal; Senanayake, Chris H.; Stringham, Rodger W.; Gupton, B. Frank; Donsbach, Kai O.; Nelson, Ryan C.; Shanahan, Charles S.

Abstract : Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this mol. relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodol. to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from D-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.

Published in: Nature Communications, Volume: 14, Issue: 1, Pages: 3059

DOI: 10.1038/s41467-023-38774-1

Authors: Kumpornsin, Krittikorn; Kochakarn, Theerarat; Yeo, Tomas ; Okombo, John ; Luth, Madeline R.; Hoshizaki, Johanna ; Rawat, Mukul; Pearson, Richard D. ; Schindler, Kyra A. ; Mok, Sachel ; Park, Heekuk ; Uhlemann, Anne-Catrin ; Jana, Gouranga P. (TCGLS Member); Maity, Bikash C. (TCGLS Member); Laleu, Benoit ; Chenu, Elodie; Duffy, James; Moliner Cubel, Sonia; Franco, Virginia; Gomez-Lorenzo, Maria G. ; Gamo, Francisco Javier ; Winzeler, Elizabeth A.; Fidock, David A. ; Chookajorn, Thanat; Lee, Marcus C. S.

Abstract: In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ∼5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines. Upon challenge with the spiroindolone PfATP4-inhibitor KAE609, high-level resistance is obtained more rapidly and at lower inocula than wild-type parasites. Selections also yield mutants with resistance to an “irresistible” compound, MMV665794 that failed to yield resistance with other strains. We validate mutations in a previously uncharacterised gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), as causal for resistance to MMV665794 and a panel of quinoxaline analogs. The increased genetic repertoire available to this “mutator” parasite can be leveraged to drive P. falciparum resistome discovery.

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 12, Issue : 33, Pages : 6507-6515

DOI : 10.1039/c4ob01047g

Author : Malhotra, Rajesh; Dey, Tushar K.; Dutta, Swarup; Basu, Sourav; Hajra, Saumen

Abstract : First regioselective ring opening of serine derived cyclic sulfamidate by hard nucleophiles like ArONa is developed, where β-elimination of serine sulfamidate ester by stronger nucleophiles is overcome by reversal of the electronic effect of the carboxylate anion. This method provides easy and direct access to a variety of N-Boc- and N-PMB protected β-aryloxy-α-amino acids with complete retention of enantiopurity in moderate to high yields.

Published in : Synthetic Communications

DOI: 10.1080/00397911.2023.2205593

Authors: Chandan K. Mahato (TCGLS Member),Subhro Mandal,Mrinalkanti Kundu (TCGLS Member)&AnimeshPramanik

Abstract: A proline-based, chiral bi-functional organocatalyst containing both pyrrolidine and oxadiazolone heterocycle, has been successfully applied for stereoselective aldol reactions. The replacement of polar -COOH group of proline with bioisostereoxadiazolone ring provides excellent solubility of this catalyst in various organic solvents compared to low soluble proline. As a result, the organocatalyst effectively catalyzed the asymmetric condensation reaction between differently substituted aromatic aldehydes and various symmetrical and unsymmetrical ketones to produce the corresponding aldol products with excellent stereoselectivities (dr: 97:3, ee>99.9%) at room temperature in open-air.