Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®

Blizzard, Timothy A.; Chen, Helen; Kim, Seongkon; Wu, Jane Y.; Bodner, Rena; Gude, Candido; Imbriglio, Jason E.; Young, Katherine; Park, Young-Whan; Ogawa, Aimie M.; Raghoobar, Susan L.; Hairston, Nichelle; Painter, Ronald E.; Wisniewski, Doug; Scapin, Giovanna; Fitzgerald, Paul J.; Sharma, Nandini; Lü, Jun; Ha, Sookhee; Hermes, Jeff; Hammond, Milton L.

doi:10.1016/j.bmcl.2013.12.101

Cited by 148 publications

(119 citation statements)

References 14 publications

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“…Relebactam (MK-7655) is an inhibitor of class A and class C β-lactamases that is in development for use in combination with imipenem-cilastatin to treat serious infections caused by β-lactamase-producing Gram-negative bacteria (26, 27). The addition of relebactam restores imipenem activity against multidrug-resistant strains of Pseudomonas aeruginosa and Enterobacteriaceae in vitro (26, 28).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

Rhee

Rizk

Calder

et al. 2018

Antimicrob Agents Chemother

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Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals.

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Section: Introductionmentioning

confidence: 99%

“…The addition of relebactam restores imipenem activity against multidrug-resistant strains of Pseudomonas aeruginosa and Enterobacteriaceae in vitro (26, 28). Relebactam decreased imipenem MICs from a range of 16 to 64 mg/liter to a range of 0.12 to 1 mg/liter for Enterobacteriaceae with KPC.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

Rhee

Rizk

Calder

et al. 2018

Antimicrob Agents Chemother

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“…Derivatization of the primary amide functionality in avibactam has led to the development of new DBO analogues [22], such as 9.1 (NXL-105) [133], 9.2 [130], 9.3 (MK-7655) [129,[131][132] and 9.4 (OP0595) [145,146] (Figure 9), some of which have antibacterial activity. In vitro studies have been carried out on these DBO-based compounds, both independently and in combination with various types of β-lactam antibacterials, including penicillins (piperacillin), cephalosporins (cefepime) and carbapenems (imipenem and meropenem) [173][174][175][176][177][178].…”

Section: Avibactam Mode Of Actionmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

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“…The choice of this heterocycle came from screening a variety of basic and neutral heterocyclic side chains, taking into account results obtained with a previous inhibitor MK‐8712 ( 56 ) 178. It was found that the addition of a basic nitrogen atom greatly helped to reduce efflux from the bacterial cell 178…”

Section: β‐Lactamase Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®

Cited by 148 publications

References 14 publications

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

Targeting Antibiotic Resistance

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