Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria

Lapointe, Guillaume; Skepper, Colin K.; Holder, Lauren M.; Armstrong, Duncan; Bellamacina, Cornelia; Blais, Johanne; Bussiere, Dirksen E.; Bian, Jianwei; Cepura, Cody; Chan, Helen; Dean, Charles R.; Pascale, Gianfranco De; Dhumale, Bhavesh; Fisher, L. Mark; Fulsunder, Mangesh; Kantariya, Bhavin; Kim, Julie; King, Serina; Kossy, Lauren; Kulkarni, Upendra; Lakshman, Jay P.; Leeds, Jennifer A.; Ling, Xiaolan; Lvov, Anatoli; Ma, Sylvia; Malekar, Swapnil A.; McKenney, David; Mergo, Wosenu; Metzger, Louis E.; Mhaske, Keshav; Moser, Heinz; Mostafavi, Mina; Namballa, Sunil; Noeske, J.; Osborne, Colin; Patel, Avnish; Patel, Darshit; Patel, Tushar M.; Piéchon, Philippe; Polyakov, Valery; Prajapati, Krunal; Prosen, Katherine R.; Reck, Folkert; Richie, Daryl L.; Sanderson, Mark; Satasia, Shailesh P.; Savani, Bhautik; Selvarajah, Jogitha; Sethuraman, Vijay A.; Shu, Wei; Thompson, Katherine; Vaarla, Krishniah; Vala, Lakhan; Veselkov, D. A.; Vo, Jason; Vora, Bhavesh; Wagner, Trixie; Wedel, Laura; Williams, S.; Yendluri, Satya; Qin, Yue; Yifru, Aregahegn; Zhang, Yong; Rivkin, Alexey

doi:10.1021/acs.jmedchem.1c00375

Cited by 14 publications

(7 citation statements)

References 103 publications

(185 reference statements)

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“…Target site mutation is a potential strategy for combating drug resistance. The identification and development of a novel class of chemicals that inhibit the two bacterial target enzymes and stabilize the DNA cleavage complexes were described recently by Lapointe et al (2021). More study into it is likely to lead to the development of novel antibiotics.…”

Section: The Antibiotic Resistance Mechanism Of E Colimentioning

confidence: 99%

Antibiotic Resistance and Mechanisms of Pathogenic Bacteria in Tubo-Ovarian Abscess

Tang

Zhou²,

Zhang³

2022

Front. Cell. Infect. Microbiol.

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A tubo-ovarian abscess (TOA) is a common type of inflammatory lump in clinical practice. TOA is an important, life-threatening disease, and it has become more common in recent years, posing a major health risk to women. Broad-spectrum antimicrobial agents are necessary to cover the most likely pathogens because the pathogens that cause TOA are polymicrobial. However, the response rate of antibiotic treatment is about 70%, whereas one-third of patients have poor clinical consequences and they require drainage or surgery. Rising antimicrobial resistance serves as a significant reason for the unsatisfactory medical outcomes. It is important to study the antibiotic resistance mechanism of TOA pathogens in solving the problems of multi-drug resistant strains. This paper focuses on the most common pathogenic bacteria isolated from TOA specimens and discusses the emerging trends and epidemiology of resistant Escherichia coli, Bacteroides fragilis, and gram-positive anaerobic cocci. Besides that, new methods that aim to solve the antibiotic resistance of related pathogens are discussed, such as CRISPR, nanoparticles, bacteriophages, antimicrobial peptides, and pathogen-specific monoclonal antibodies. Through this review, we hope to reveal the current situation of antibiotic resistance of common TOA pathogens, relevant mechanisms, and possible antibacterial strategies, providing references for the clinical treatment of drug-resistant pathogens.

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Section: The Antibiotic Resistance Mechanism Of E Colimentioning

confidence: 99%

Antibiotic Resistance and Mechanisms of Pathogenic Bacteria in Tubo-Ovarian Abscess

Tang

Zhou²,

Zhang³

2022

Front. Cell. Infect. Microbiol.

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“…The still ongoing story [145] of pleuromutilins illustrates again how long a successful discovery process can take. Concerning one last class of large spectrum antibiotics, there are noteworthy reports which describe the extensive rescaffolding efforts aiming at the discovery of original fluoroquinolone-like antibiotics [146][147][148]. The recently reviewed [149] discoveries of the bicyclic nitroimidazoles depicted in Figure 5: pretomanid (18) and delamanid (19) as new drugs to treat tuberculosis is also of interest.…”

Section: Hit To Lead Recent Success Stories In Antibacterialsmentioning

confidence: 99%

On drug discovery against infectious diseases and academic medicinal chemistry contributions

Janin¹

2022

Beilstein J. Org. Chem.

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This perspective is an attempt to document the problems that medicinal chemists are facing in drug discovery. It is also trying to identify relevant/possible, research areas in which academics can have an impact and should thus be the subject of grant calls. Accordingly, it describes how hit discovery happens, how compounds to be screened are selected from available chemicals and the possible reasons for the recurrent paucity of useful/exploitable results reported. This is followed by the successful hit to lead stories leading to recent and original antibacterials which are, or about to be, used in human medicine. Then, illustrated considerations and suggestions are made on the possible inputs of academic medicinal chemists. This starts with the observation that discovering a “good” hit in the course of a screening campaign still rely on a lot of luck – which is within the reach of academics –, that the hit to lead process requires a lot of chemistry and that if public–private partnerships can be important throughout these stages, they are absolute requirements for clinical trials. Concerning suggestions to improve the current hit success rate, one academic input in organic chemistry would be to identify new and pertinent chemical space, design synthetic accesses to reach these and prepare the corresponding chemical libraries. Concerning hit to lead programs on a given target, if no new hits are available, previously reported leads along with new structural data can be pertinent starting points to design, prepare and assay original analogues. In conclusion, this text is an actual plea illustrating that, in many countries, academic research in medicinal chemistry should be more funded, especially in the therapeutic area neglected by the industry. At the least, such funds would provide the intensive to secure series of hopefully relevant chemical entities which appears to often lack when considering the results of academic as well as industrial screening campaigns.

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“…Around 60% of the suffering in patients is caused due to different types of infections acquired during treatment in hospitals. , To treat these infections, several classes of antimicrobial agents have frequently been administrated by medical practitioners. , However, the excessive usage of these antimicrobial agents has created resistance in microorganisms. , Consequently, the conventional antibiotics including different types of β-lactams work with reduced potency and considerably enhanced morality rate among patients . Due to the inferior potency of commercially available antibiotics, microbial infection in patients and animals has become extremely challenging to treat. − As a result, the hospitalized time of diseased persons has been stretched longer, with higher treatment charges as well as additional suffering for patients . Moreover, the increment in the death rate is unavoidable in immune-deficient patients with elemental health issues. , Up to now, different endeavors including modification in antibiotic structures as well as integration of antimicrobes with high productivity rate have been administrated to combat bacterial resistance .…”

Section: Introductionmentioning

confidence: 99%

3-Methoxyazetidin-2-one Functionalized CuO–CB Microfibrils: A Drug Formulation with Controlled Release and Enhanced Synergistic Antibacterial Activities

Vijeata

Chaudhary

Bhalla

et al. 2023

ACS Appl. Bio Mater.

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trans-1-(4′-Methoxyphenyl)-3-methoxy-4-phenyl 3-methoxyazetidin-2-one (or 3-methoxyazetidin-2-one) is one of the important β-lactam derivatives with an ample range of bacterial activities yet few restrictions. To enhance the competency of the chosen 3-methoxyazetidin-2-one, microfibrils composed of copper oxide (CuO) and filter scraps of cigarette butts (CB) were chosen in the current work for developing a potential release formulation. The preparation of CuO-CB microfibrils required a simple reflux technique and a subsequent calcination treatment. The loading of 3-methoxyazetidin-2-one was processed via controlled magnetic stirring followed by centrifugation with microfibrils of CuO-CB. To confirm the loading efficiency, the 3methoxyazetidin-2-one@CuO-CB complex was analyzed by scanning electron microscopy, transmission electron microscopy, and infrared spectroscopy. Compared to the CuO nanoparticles, the release profile of CuO-CB microfibrils indicates only 32% of the drug release in the first 1 h at pH 7.4. As a model organism, E. coli has been utilized for in vitro drug release dynamic studies. Based on the observed drug release data, it was found that the prepared formulation evades premature drug release and triggers the on-demand release of drug inside bacterial cells. The controlled drug release by 3-methoxyazetidin-2-one@CuO-CB microfibrils over a period of 12 h further ascertained the excellent bactericide delivery mechanism to combat deadly bacterial resistance. Indeed, this study provides a strategy to combat antimicrobial resistance and eradicate bacterial disease via nanotherapeutics.

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Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria

Cited by 14 publications

References 103 publications

Antibiotic Resistance and Mechanisms of Pathogenic Bacteria in Tubo-Ovarian Abscess

Antibiotic Resistance and Mechanisms of Pathogenic Bacteria in Tubo-Ovarian Abscess

On drug discovery against infectious diseases and academic medicinal chemistry contributions

3-Methoxyazetidin-2-one Functionalized CuO–CB Microfibrils: A Drug Formulation with Controlled Release and Enhanced Synergistic Antibacterial Activities

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