Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections

Mitton‐Fry, Mark J.; Arcari, Joel T.; Brown, Matthew F.; Casavant, Jeffrey; Finegan, Steven M.; Flanagan, Mark E.; Gao, Hongying; George, D. M.; Gerstenberger, Brian S.; Han, Seungil; Hardink, Joel R.; Harris, Thomas M.; Hoang, Thuy; Huband, Michael D.; Irvine, Rebecca; Lall, Manjinder S.; Lemmon, M. Megan; Li, Chao; Lin, Jian; McCurdy, Sandra P.; Mueller, John P.; Mullins, Lisa; Niosi, Mark; Noe, Mark C.; Pattavina, David; Penzien, Joseph; Plummer, Mark S.; Risley, Hud; Schuff, Brandon P.; Shanmugasundaram, Veerabahu; Starr, Jeremy T.; Sun, Jianmin; Winton, Jennifer; Young, Jennifer A.

doi:10.1016/j.bmcl.2012.07.005

Cited by 17 publications

(20 citation statements)

References 34 publications

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“…7 and Table 2). 68 Several of these compounds worked in combination with aztreonam or meropenem to lower MIC values to the susceptible range against P aeruginosa and also possessed efficacy in a mouse pneumonia model of infection. The siderophore monobactams were modified to increase the length of the R2 side chain with linkers resulting in expansion of activity against K pneumoniae , E coli , and A baumannii , including P aeruginosa carrying a bla MBL ; these compounds target the PBPs and evade MBL activity.…”

Section: Monobactams and Derivatives In Preclinical Developmentmentioning

confidence: 99%

New β-Lactamase Inhibitors in the Clinic

Papp-Wallace

2016

Infectious Disease Clinics of North America

146

129

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Section: Monobactams and Derivatives In Preclinical Developmentmentioning

confidence: 99%

New β-Lactamase Inhibitors in the Clinic

Papp-Wallace

2016

Infectious Disease Clinics of North America

146

129

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“…In 2012, Pfizer researchers published novel siderophore‐linked monobactams 166 with in vitro and in vivo antimicrobial activity against MDR Gram‐negative pathogens (Fig. ) . The decision to incorporate the siderophore to the 4‐position of the β‐lactam was based on the fact that such 4‐substituted derivatives showed enhanced aqueous stability.…”

Section: Siderophore‐conjugated Monocyclic β‐Lactamsmentioning

confidence: 99%

“…As linkers, isoxazole and oxazole proved to be the most optimal and compound 168 showed the best overall characteristics. Despite not being the most active derivative in the series, it showed reasonable pharmacokinetic properties, low intrinsic clearance, and favorable in vivo efficacy properties …”

Section: Siderophore‐conjugated Monocyclic β‐Lactamsmentioning

confidence: 99%

“…40). 204 The decision to incorporate the siderophore to the 4-position of the β-lactam was based on the fact that such 4-substituted derivatives showed enhanced aqueous stability. The first compound representing a breakthrough was compound 167, as its profiling against various bacterial strains revealed potent MIC 90 values against both P. aeruginosa and E. coli (Fig.…”

Section: Siderophore-conjugated Monobactamsmentioning

confidence: 99%

“…Despite not being the most active derivative in the series, it showed reasonable pharmacokinetic properties, low intrinsic clearance, and favorable in vivo efficacy properties. 204 The same research group later published another chemically diverse set of analogues, designed on the basis of cocrystal structures of several ring-opened β-lactams with PBP3 from P. aeruginosa. Significant effort was aimed at the linker motifs connecting the β-lactam core to the pyridone moiety, as it was established that a wide range of linker groups can be accommodated in this region.…”

Section: Siderophore-conjugated Monobactamsmentioning

confidence: 99%

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Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Decuyper

Jukič

Sosič

et al. 2017

Medicinal Research Reviews

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Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial β-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β-lactamase stability. In that respect, our review covers the updates in the field of monocyclic β-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β-lactams, classified according to their N-substituent, and the associated antibacterial or β-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic β-lactams.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections

Cited by 17 publications

References 34 publications

New β-Lactamase Inhibitors in the Clinic

New β-Lactamase Inhibitors in the Clinic

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Medicinal Chemistry of β‐Lactam Antibiotics

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