Article
Microbiology
Dmitrii Shiriaev, Alina A. Sofronova, Ekaterina A. Berdnikovich, Dmitrii A. Lukianov, Ekaterina S. Komarova, Valeriya Marina, Yuliya Zakalyukina, Mikhail Biryukov, Tinashe P. Maviza, Yan A. Ivanenkov, Petr Sergiev, Ilya A. Osterman, Olga A. Dontsova
Summary: Bacterial type II topoisomerases are targets of many antibiotics, and some bacteria easily develop resistance to fluoroquinolones through mutations in DNA gyrase or topoisomerase IV genes. Nybomycins are compounds that selectively inhibit growth of some Gram-positive FQ-resistant bacteria, but further research is needed on their effectiveness against Gram-negative species.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Chemistry, Medicinal
Martina Durcik, Akos Nyerges, Ziga Skok, Darja Gramec Skledar, Jurij Trontelj, Nace Zidar, Janez Ilas, Anamarija Zega, Cristina D. Cruz, Paivi Tammela, Martin Welin, Yengo R. Kimbung, Dorota Focht, Ondrej Benek, Tamas Revesz, Gabor Draskovits, Petra Eva Szili, Lejla Daruka, Csaba Pal, Danijel Kikelj, Lucija Peterlin Masic, Tihomir Tomasic
Summary: The rise in multidrug-resistant bacteria highlights the need for new antibacterial agents less prone to resistance. Compounds simultaneously inhibiting multiple bacterial targets, like 31h, show promising antibacterial activities without cytotoxicity and potency against various pathogens, including those resistant to other drugs. The structural derivatives of 31h could represent a step towards clinically efficacious multitargeting antimicrobials resilient to existing antimicrobial resistance.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Soziema E. E. Dauda, Jessica A. A. Collins, Jo Ann W. Byl, Yanran Lu, Jack C. C. Yalowich, Mark J. J. Mitton-Fry, Neil Osheroff
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibiotics that target gyrase and topoisomerase IV. NBTIs can induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, some dioxane-linked amide NBTIs have been found to induce double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. The compound OSUAB-185 induces single-stranded and suppressed double-stranded DNA breaks mediated by Neisseria gonorrhoeae gyrase, while stabilizing both single- and double-stranded DNA breaks mediated by topoisomerase IV.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Medicinal
Scott Grossman, Colin W. G. Fishwick, Martin J. McPhillie
Summary: Increases in antibiotic usage have led to antimicrobial resistance and reduced effectiveness of antimicrobial treatments. Researchers have been looking for new bioactive molecules to inhibit bacterial topoisomerases through non-intercalating agents and alternative mechanisms, such as allosteric site inhibitors and ATPase domain inhibitors, to overcome bacterial resistance to fluoroquinolones.
Article
Chemistry, Medicinal
Firas O. A. Frejat, Yaquan Cao, Lihong Wang, Hongjin Zhai, Ahmed H. Abdelazeem, Hesham A. M. Gomaa, Bahaa G. M. Youssif, Chunli Wu
Summary: A series of hybridized pyrrolidine compounds with a 1,2,4-oxadiazole moiety were synthesized as potential inhibitors against DNA gyrase and topoisomerase IV. Compounds 16 and 17 showed the strongest inhibitory effects against both enzymes, with compound 17 outperforming novobiocin in MIC assays against E. coli. The results of this study support the promising approach of developing potent leads for further optimization.
ARCHIV DER PHARMAZIE
(2022)
Article
Chemistry, Medicinal
Maja Kokot, Marko Anderluh, Martina Hrast, Nikola Minovski
Summary: The emergence of bacterial resistance has created a need for new and effective antibacterial agents. Novel bacterial topoisomerase inhibitors (NBTIs) represent a promising class of antibacterial agents that can target different bacterial species with varying potencies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Eddy E. Alfonso, Rogelio Troche, Zifang Deng, Thirunavukkarasu Annamalai, Prem Chapagain, Yuk-Ching Tse-Dinh, Fenfei Leng
Summary: The study identified effective bacterial DNA gyrase inhibitors that exhibit strong antimicrobial activities against E. coli and Staphylococcus aureus.
Article
Infectious Diseases
Alasdair P. Macgowan, M. L. G. Attwood, Alan R. Noel, R. Barber, Zachary Aron, Timothy J. Opperman, Elizabeth Grimsey, Jack Stone, Vito Ricci, L. J. Piddock
Summary: This study investigated the pharmacodynamic characteristics of efflux pump inhibitors (EPIs) in Escherichia coli through in vitro experiments and gene sequencing. The results showed that the AUC of chlorpromazine and PA beta N was most closely related to the reduction in bacterial load, while the T > threshold of MBX-4191 was the driver for bacterial load reduction. No changes in population profiles were observed with the combination of ciprofloxacin + EPIs, but mutations were detected in gyrA, gyrB, and marR.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2023)
Article
Microbiology
Anna Olina, Aleksei Agapov, Denis Yudin, Dmitry Sutormin, Alina Galivondzhyan, Anton Kuzmenko, Konstantin Severinov, Alexei A. Aravin, Andrey Kulbachinskiy
Summary: This study demonstrates that two cyanobacterial pAgos, SeAgo and LrAgo, can assist DNA replication and facilitate cell division in the presence of topoisomerase inhibitors in Escherichia coli. They are specifically loaded with small guide DNAs derived from the replication termination region and protect the cells from the action of the gyrase inhibitor ciprofloxacin, suggesting that they help to complete DNA replication and/or repair gyrase-induced breaks.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Johanne Blais, Charles R. Dean, Guillaume Lapointe, Jennifer A. Leeds, Sylvia Ma, Laura Morris, Heinz E. Moser, Colin S. Osborne, Katherine R. Prosen, Daryl Richie, Colin Skepper, Katherine Thompson, Jason Vo, Qin Yue, Alexey Rivkin
Summary: CUO246 is a novel DNA gyrase/topoisomerase IV inhibitor with broad-spectrum in vitro activity against Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens, including quinolone-resistant strains. It inhibits both DNA gyrase and topoisomerase IV and exhibits potent bactericidal activity. In a mouse model, it shows efficacy against S. aureus infections. CUO246 may be a useful treatment option for acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Biochemistry & Molecular Biology
Paul Villain, Ryan Catchpole, Patrick Forterre, Jacques Oberto, Violette da Cunha, Tamara Basta
Summary: This study reveals the evolutionary history of DNA gyrase in Archaea using phylogenomic approaches and sequence datasets. The results suggest that DNA gyrase was introduced into Euryarchaeal group II through horizontal gene transfer from bacterial ancestors. Furthermore, DNA gyrase has spread to other Archaea lineages through rare horizontal gene transfers. The study also shows the co-evolution of DNA gyrase and Topoisomerase VI in Archaea.
MOLECULAR BIOLOGY AND EVOLUTION
(2022)
Article
Microbiology
Aiko Masuko, Iichiro Takata, Kiyoko Fujita, Hirotoshi Okumura, Fumihito Ushiyama, Hideaki Amada, Hiroyuki Sugiyama
Summary: The novel DNA gyrase/topoisomerase IV inhibitor TP0480066 showed potent in vitro and in vivo activities against multidrug-resistant Neisseria gonorrhoeae strains, with no cross-resistance observed with ciprofloxacin. It also demonstrated low frequencies of spontaneous resistance and strong bactericidal activity, suggesting it may be a candidate antimicrobial agent for gonococcal infections.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Multidisciplinary Sciences
Yuh Morimoto, Yoshifumi Aiba, Kazuhiko Miyanaga, Tomomi Hishinuma, Longzhu Cui, Tadashi Baba, Keiichi Hiramatsu
Summary: This study discovered five flavonoids (quercetin, luteolin, kaempferol, baicalein, and CID12261165) that show similar antimicrobial activity against fluoroquinolone-resistant Staphylococcus aureus. Among them, CID12261165 was the most effective with MIC values of <= 4 mg/L against quinolone-resistant S. aureus strains. CID12261165 also inhibited quinolone-resistant Enterococci with an MIC value of 8 mg/L. The study discusses the discrepancies in the interpretation of antimicrobial activities of flavonoids and the possible reasons for the preservation of wild-type DNA gyrase.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Xudong Ouyang, Jelmer Hoeksma, Ronnie J. M. Lubbers, Tjalling K. Siersma, Leendert W. Hamoen, Jeroen den Hertog
Summary: Antimicrobial resistance poses a major threat to human health, and understanding the mechanism of action of antimicrobial drugs is crucial for patient care and the discovery of new antimicrobials. The DBMI method, utilizing fluorescence imaging, allows for rapid classification of the mechanism of action of antimicrobials.
SCIENTIFIC REPORTS
(2022)
Article
Microbiology
Jeewan Thapa, Joseph Yamweka Chizimu, Soyoka Kitamura, Mwangala Lonah Akapelwa, Pondpan Suwanthada, Nami Miura, Jirachaya Toyting, Tomoyasu Nishimura, Naoki Hasegawa, Yukiko Nishiuchi, Stephen V. Gordon, Chie Nakajima, Yasuhiko Suzuki
Summary: This study found that amino acid substitutions in the gyrA of M. avium contribute to fluoroquinolone resistance, shedding light on the role of these substitutions in the development of resistance.
MICROBIOLOGY SPECTRUM
(2023)
Article
Oncology
Lisa M. Oppegard, Justine L. Delgado, Chaitanya A. Kulkarni, Tyrell R. Towle, Delaney E. Hart, Bridget P. Williams, Sarah R. C. Lentz, Beverly J. Norris, Craig M. Flory, Robert J. Schumacher, Daryl J. Murry, Robert J. Kerns, Hiroshi Hiasa
INVESTIGATIONAL NEW DRUGS
(2019)
Article
Biochemistry & Molecular Biology
Chaitanya A. Kulkarni, Paul S. Brookes
ANTIOXIDANTS & REDOX SIGNALING
(2019)
Article
Chemistry, Medicinal
Justine L. Delgado, Sarah R. C. Lentz, Chaitanya A. Kulkarni, Pratik R. Chheda, Hailey A. Held, Hiroshi Hiasa, Robert J. Kerns
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Biology
Chaitanya A. Kulkarni, Sergiy M. Nadtochiy, Leslie Kennedy, Jimmy Zhang, Sophea Chhim, Hanan Alwaseem, Elizabeth Murphy, Dragony Fu, Paul S. Brookes
Article
Biochemistry & Molecular Biology
Alexander S. Milliken, Chaitanya A. Kulkarni, Paul S. Brookes
Article
Chemistry, Medicinal
Bader I. Huwaimel, Myla Bhakta, Chaitanya A. Kulkarni, Alexander S. Milliken, Feifei Wang, Aimin Peng, Paul S. Brookes, Paul C. Trippier
Summary: Study investigated benzothiadiazine derivatives for CII inhibition and their impact on cancer cells, identifying compounds with greater antineoplastic effect in triple-negative breast cancer cells compared to clinical agents. No correlation found between cytotoxicity and CII inhibition, suggesting undefined mechanism of action for this scaffold.
Article
Chemistry, Medicinal
Chaitanya A. Kulkarni, Brian D. Fink, Bettine E. Gibbs, Pratik R. Chheda, Meng Wu, William Sivitz, Robert J. Kerns
Summary: The study identified an inert mitochondria-targeting carrier by modifying the structure of TPP+, which successfully eliminated uncoupling activity, prevented dissipation of mitochondrial membrane potential, and did not negatively affect cargo delivery to mitochondria.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Susheel K. Gunasekar, Litao Xie, Ashutosh Kumar, Juan Hong, Pratik R. Chheda, Chen Kang, David M. Kern, Chau My-Ta, Joshua Maurer, John Heebink, Eva E. Gerber, Wojciech J. Grzesik, Macaulay Elliot-Hudson, Yanhui Zhang, Phillip Key, Chaitanya A. Kulkarni, Joseph W. Beals, Gordon Smith, Isaac Samuel, Jessica K. Smith, Peter Nau, Yumi Imai, Ryan D. Sheldon, Eric B. Taylor, Daniel J. Lerner, Andrew W. Norris, Samuel Klein, Stephen G. Brohawn, Robert Kerns, Rajan Sah
Summary: SWELL1 channel modulators represent a novel therapeutic approach for treating Type 2 diabetes and associated liver steatosis by enhancing insulin sensitivity and secretion. These modulators improve SWELL1-dependent systemic metabolism and hold promise for future treatment of diabetes and nonalcoholic fatty liver disease.
NATURE COMMUNICATIONS
(2022)
Meeting Abstract
Cardiac & Cardiovascular Systems
Chaitanya A. Kulkarni, Alexander S. Milliken, Paul S. Brookes
CIRCULATION RESEARCH
(2019)
Article
Pharmacology & Pharmacy
Yumi Imai, Brian D. Fink, Joseph A. Promes, Chaitanya A. Kulkarni, Robert J. Kerns, William I. Sivitz
PHARMACOLOGY RESEARCH & PERSPECTIVES
(2018)
Article
Pharmacology & Pharmacy
Brian D. Fink, Deng Fu Guo, Chaitanya A. Kulkarni, Kamal Rahmouni, Robert J. Kerns, William I. Sivitz
PHARMACOLOGY RESEARCH & PERSPECTIVES
(2017)
Meeting Abstract
Chemistry, Multidisciplinary
Chaitanya Kulkarni, Tyrell Towle, Robert Kerns
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
(2016)
Article
Pharmacology & Pharmacy
Brian D. Fink, Judith A. Herlein, Deng Fu Guo, Chaitanya Kulkarni, Benjamin J. Weidemann, Liping Yu, Justin L. Grobe, Kamal Rahmouni, Robert J. Kerns, William I. Sivitz
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2014)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)