In vitro and in vivo activity of GT-1, a novel siderophore cephalosporin, and GT-055, a broad-spectrum β-lactamase inhibitor, against biothreat and ESKAPE pathogens

Halasohoris, Stephanie; Scarff, Jennifer M.; Pysz, Lisa M; Lembirik, Sanae; Lemmon, M. Megan; Biek, Donald; Hannah, Brendan; Zumbrun, Steven D.; Panchal, Rekha G.

doi:10.1038/s41429-021-00472-9

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…Table 4 reports the details of a preclinical trial that investigated the effects of GT-1 and GT-1/GT-055 in mouse infection models of B. pseudomallei and Y. pestis. Collectively, the efficacy of the combination was like that of ciprofloxacin in the Y. pestis model, while it was less effective in the B. pseudomallei infection model [113].…”

Section: Ant-3310mentioning

confidence: 88%

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

Alfei

Schito

2022

Pharmaceuticals

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β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel antibiotics are in development, a current clinical approach to limit this phenomenon consists of administering proper combinations of β-lactam antibiotics (BLAs) and β-lactamase inhibitors (BLEsIs). Unfortunately, while few clinically approved BLEsIs are capable of inhibiting most class-A and -C serine β-lactamases (SBLEs) and some carbapenemases of class D, they are unable to inhibit most part of the carbapenem hydrolyzing enzymes of class D and the worrying metallo-β-lactamases (MBLEs) of class B. Particularly, MBLEs are a set of enzymes that catalyzes the hydrolysis of a broad range of BLAs by a zinc-mediated mechanism, and currently no clinically available molecule capable of inhibiting MBLEs exists. Additionally, new types of alarming “superbugs”, were found to produce the New Delhi metallo-β-lactamases (NDMs) encoded by increasing variants of a plasmid-mediated gene capable of rapidly spreading among bacteria of the same species and even among different species. Particularly, NDM-1 possesses a flexible hydrolysis mechanism that inactivates all BLAs, except for aztreonam. The present review provides first an overview of existing BLAs and the most clinically relevant BLEs detected so far. Then, the BLEsIs and their most common associations with BLAs already clinically applied and those still in development are reviewed.

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Section: Ant-3310mentioning

confidence: 88%

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

Alfei

Schito

2022

Pharmaceuticals

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“…Exploring siderophore-β-lactam conjugates led to the development of a novel siderophore cephalosporin (25) that was demonstrated to be effective against ESKAPE pathogens [218]. Compound 25 consists of a dihydroxypyridone siderophore conjugated to a modified aminothiazoylglycyl cephalosporin.…”

Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

“…Among these compounds, 24 showed potent activity against the multi-drug-resistant (MDR) S. aureus NRS70 strain (MIC values of 3.13 µg/mL). (21 [211], 22 [196], 23 [212], LYS228 [213], 24 [217], 25 [218], 26 [219], 27 [152], 28 [220], ETX0462 [221], 29 [222], 30 [223]).…”

Section: New Transpeptidase Inhibitor Scaffoldsmentioning

confidence: 99%

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Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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“…(МПК 50 (64) = 0,25-0,5 мг/л), S. marcescens (МПК 50 (64) = 2 мг/л) и K. aerogenes (МПК 50 (64) = 0,5 мг/л), чем цефтазидим, цефтриаксон и ципро флоксацин [148]. В другой ра боте [151] были проведены исследования in vivo, кото рые показали, что эффективность лечения мышей, ин фицированных Yersinia pestis, с помощью GT1 64 была ниже эффективности препарата сравнения -ципрофлок сацина (мыши, которые получали низкие дозы GT1 по гибали от инфекции на седьмой день, в случаях, когда мыши получали GT1 в дозе 60 или 200 мг/кг, их вы живаемость составляла 90%, в то время как выживае мость мышей, которые получали ципрофлоксацин в дозе 30 мг/кг, была 100%). В марте 2019 г. в Австралии было инициировано исследование I фазы препарата GT1, но позднее данное исследование было остановлено в связи с гепатотоксичностью, препятствовавшей достижению эффективной терапевтической дозы [115,152].…”

Section: конъюгаты сидерофор-антибиотик содержащие дигидропиридоновый...unclassified

Siderophore‑antibiotic conjugates: structural diversity and antibacterial activity

Chernyshov

Kuzovlev

Cherepanova

et al. 2022

CMAC

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Due to uncontrolled growth of antimicrobial resistance, in the near future humanity may return to the «pre-antibiotic era» with no reliable antimicrobial therapy even for previously easily treatable infectious diseases. One of possible solutions is improved delivery of antibiotics to antibiotic-resistant bacterial strains by conjugating them with siderophores (small molecules secreted by microorganisms to absorb essential Fe(III)). The siderophore-modified antibiotic (sideromycin), like a Trojan horse, permeates the bacterial cell as a complex with Fe(III), allowing the antibiotic to reach its biological target. In this review, we describe the structural diversity of siderophore-antibiotic conjugates with the focus on the structure of sideromycin as well as on the relationship between the structure of sideromycin and its antibacterial activity. We analyze main representatives of various classes of siderophores; the structural diversity of sideromycins and their antibacterial activity discussed in detail.

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In vitro and in vivo activity of GT-1, a novel siderophore cephalosporin, and GT-055, a broad-spectrum β-lactamase inhibitor, against biothreat and ESKAPE pathogens

Cited by 8 publications

References 20 publications

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Siderophore‑antibiotic conjugates: structural diversity and antibacterial activity

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