Pursuit of next-generation glycopeptides: a journey with vancomycin

Acharya, Yash; Dhanda, Geetika; Sarkar, Paramita; Haldar, Jayanta

doi:10.1039/d1cc06635h

Cited by 18 publications

(21 citation statements)

References 75 publications

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“…The search for new glycopeptide antibiotics with improved chemotherapeutic properties is a current focus of antimicrobial drug development [1,[8][9][10]. This is due to three main factors: the spreading of strain resistance to natural glycopeptides, restrictions for the indication of use due to their short half-life, rapid excretion, low accumulation in certain tissues, and the presence of side effects [11].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats

et al. 2022

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Glycopeptide antibiotics have side effects that limit their clinical use. In view of this, the development of glycopeptides with improved chemotherapeutic properties remains the main direction in the search for new antibacterial drugs. The objective of this study was to evaluate the toxicological characteristics of new semi-synthetic glycopeptide flavancin. Acute and chronic toxicity of antibiotic was evaluated in Wistar rats. The medium lethal dose (LD50) and the maximum tolerated doses (MTD) were calculated by the method of Litchfield and Wilcoxon. In the chronic toxicity study, the treatment regimen consisted of 15 daily intraperitoneal injections using two dosage levels: 6 and 10 mg/kg/day. Total doses were equivalent to MTD or LD50 of flavancin, respectively. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that no clinical-laboratory signs of toxicity were found after 15 daily injections of flavancin at a total dose close to the MTD or LD50. The pathomorphological study did not reveal any lesions on the organ structure of animals after low-dose administration of flavancin. Thus, flavancin favorably differs in terms of toxicological properties from the glycopeptides currently used in the clinic.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats

et al. 2022

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“…In addition to the chemical modifications associated with the clinically used semisynthetic glycopeptide antibiotics described above, many other approaches have been explored toward the development of novel semisynthetic glycopeptides. For extensive reviews on such glycopeptide derivatives, including discoveries before 2014, we refer the reader to the previous literature. − The present Review focuses on recent advancements in the discovery of new semisynthetic glycopeptide antibiotics reported in the interval between 2014 and the present. The structural modifications made in generating novel semisynthetic glycopeptides occur largely at four defined positions: the vancosamine primary amino group (Vv), the C-terminus (Vc), the N-terminus (Vn), and the resorcinol moiety (Vr) (Figure ).…”

Section: Recent Developments In Semisynthetic Glycopeptide Antibioticsmentioning

confidence: 99%

“…To date, a number of reviews have been published on the broad topic of the glycopeptide antibiotics. 10 − 17 In this Review we provide an updated overview of recent advancements in the field, specifically as relates to the development of novel semisynthetic glycopeptides spanning the period from 2014 to today.…”

Section: Introduction: Antimicrobial Resistance and Glycopeptide Anti...mentioning

confidence: 99%

“…From the time of its discovery, vancomycin’s structural complexity tantalized synthetic chemists, posing a monumental challenge that was ultimately met in the late 1990s, when a series of total syntheses were reported. − In the years since, vancomycin has continued to inspire total synthesis efforts most notably aimed at generating new analogues to address and understand resistance. − While total synthesis can provide access to glycopeptide variants otherwise unavailable in nature, semisynthesis currently presents the most practical means for accessing novel analogues in quantities suitable for clinical development. To date, a number of reviews have been published on the broad topic of the glycopeptide antibiotics. − In this Review we provide an updated overview of recent advancements in the field, specifically as relates to the development of novel semisynthetic glycopeptides spanning the period from 2014 to today.…”

Section: Introduction: Antimicrobial Resistance and Glycopeptide Anti...mentioning

confidence: 99%

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Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

2022

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The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine’s capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.

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“…Together with the discovery of penicillin, sulphonamides (sulfa drugs), and microbial natural products as potential therapeutic agents against multiple bacterial infections, two parallel lines of antibiotic discovery programs were in force in the forthcoming decades. Antibiotics originating from semisynthetic methods and natural products of microbial origin were fruitful in yielding structurally variable antibiotic classes [4] such as BLs, tetracyclines, aminoglycosides [18], macrolides [19], glycopeptides [20], and quinolones [21], among others [7]. Nevertheless, the pace of drug discovery slowed down after 1962 and onwards, which was perhaps due to the efforts to tailor existing structural scaffolds, resulting in the successful comprehension of the resistance that originates in bacteria from time to time [22].…”

Section: Introductionmentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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Pursuit of next-generation glycopeptides: a journey with vancomycin

Abstract: Vancomycin, a blockbuster antibiotic of the glycopeptide class, has been a life-saving therapeutic against multidrug-resistant Gram-positive infections. The emergence of glycopeptide resistance has however enunciated the need to develop credible...

Cited by 18 publications

References 75 publications

Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats

Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

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