Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1

Liu, Xiaolong; Yang, Ke‐Wu; Zhang, Yuejuan; Ge, Ying; Yang, Xiang; Chang, Yanan; Oelschlaeger, Peter

doi:10.1016/j.bmcl.2016.08.048

Cited by 17 publications

(14 citation statements)

References 24 publications

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“…With the carbamyl oxygen acting as an additional ligand, 5 is effectively a chelating agent of the two Zn(II) ions, especially Zn2. Such a chelating effect was not observed previously with the amino acid thioesters, 24,25 possibly due to the closer proximity of the thioester oxygen to the carboxylate group in those compounds, not allowing for enough conformational freedom. The addition of a methylene group in the thioethers presented here seems to provide the proper geometry for chelation.…”

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confidence: 59%

“…24 That scaffold was subsequently optimized to yield more potent L1 inhibitors. 25 Also, our studies revealed that azolylthioacetamides with an acylamino group are potential broad-spectrum inhibitors of MβLs. 26,27 The earlier mentioned amino acid mercaptoacetic acid thioesters were potent inhibitors of L1, a subclass B3MβL, but were less potent against other, more clinically important MβLs tested.…”

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confidence: 67%

“…The carboxylate of all three compounds acts as a bridging ligand of the two Zn(II) ions and forms a hydrogen bond with Ser221, tightly anchoring these inhibitors in the active site, as seen previously with amino acid thioesters. 24,25 The hydrogen of the carbamyl group also forms a hydrogen bond with Tyr32 in all three complexes. The substituent on the phenyl ring seems to affect the orientation of the ring and the adjacent carbamyl group, orienting the carbonyl oxygen toward the two Zn(II) ions in the L1/5 complex at distances of 3.2 and 3.3 Å (enlarged view in panel D), but not in the other two complexes, providing a rationale for the lower IC 50 value observed with this compound.…”

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confidence: 94%

“…Docking studies indicate that the carboxyl group may coordinate the two Zn(II) ions in the active site and hydrogen bond with Ser221 of L1, while the carbamyl group oxygen may act as an additional ligand in the most potent compound 5, thus rendering the inhibitor a chelating agent, which was not observed with the previously observed thioesters. 24,25 Cytotoxicity tests revealed that 1, 5, 7, and 16 did not affect the viability of mammalian cells at a concentration of up to 400 μM. This was expected due to the decreased likelihood of thioethers to be hydrolyzed, which could result in toxic thiols.…”

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confidence: 98%

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Carbamylmethyl Mercaptoacetate Thioether: A Novel Scaffold for the Development of L1 Metallo-β-lactamase Inhibitors

Chang

Yang

Zhang

et al. 2017

ACS Med. Chem. Lett.

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Given the clinical importance of metallo-β-lactamases (MβLs), a new scaffold, N-substituted carbamylmethyl mercaptoacetate thioether, was constructed. The obtained molecules - inhibited MβLs from all three subclasses, but preferentially L1 from subclass B3. Compound with a-carboxyphenyl substituent exhibited the broadest spectrum with at least 70% inhibition of enzymes from all subclasses at 100 μM, while compound with a-methylphenyl substituent was the most potent inhibitor of any individual enzyme, with 97% inhibition at 100 μM and an IC value of 0.41 μM against L1. Isothermal titration calorimetry assays corroborate findings from UV-vis spectrophotometric assays that the inhibition of L1 by is dose-dependent. Docking studies suggest that the carboxyl group, the sulfide atom, and the carbonyl group of the carbamyl coordinate Zn2 in a chelating fashion. Using cells expressing L1, and were able to decrease cefazolin minimum inhibitory concentration 8-fold.

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confidence: 59%

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confidence: 67%

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confidence: 94%

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confidence: 98%

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Carbamylmethyl Mercaptoacetate Thioether: A Novel Scaffold for the Development of L1 Metallo-β-lactamase Inhibitors

Chang

Yang

Zhang

et al. 2017

ACS Med. Chem. Lett.

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“…Other MBL inhibitors have been reported (28)(29)(30)(31)(32)(33)(34)(35), many of which display good in vitro activity but have not been shown to be efficacious in animal infection models. An exception to this is the natural product aspergillomarasmine A (35), a strong metal ion chelator whose further development is likely to be limited by toxicity (the 50% lethal dose [LD 50 ] in mice is 159.8 mg/kg) (36).…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae

Everett¹,

Sprynski²,

Coelho³

et al. 2018

Antimicrob Agents Chemother

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Infections caused by carbapenem-resistant (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine β-lactamases (SBLs; e.g., KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of β-lactam antibiotics with β-lactamase inhibitors are active only against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of meropenem (MEM) against a broad range of MBL-producing CRE and restore its efficacy against an NDM-1-producing strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor-carbapenem combination. This would complement the existing weaponry against CRE and address an important and growing unmet medical need.

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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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Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1

Cited by 17 publications

References 24 publications

Carbamylmethyl Mercaptoacetate Thioether: A Novel Scaffold for the Development of L1 Metallo-β-lactamase Inhibitors

Carbamylmethyl Mercaptoacetate Thioether: A Novel Scaffold for the Development of L1 Metallo-β-lactamase Inhibitors

Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae

Medicinal Chemistry of β‐Lactam Antibiotics

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