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DOI 10.1038/s41557-021-00831-x

Медицинская библиотека · Nature chemistry · 2021

Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors.

Brem Jürgen, Panduwawala Tharindi, Hansen Jon Ulf, Hewitt Joanne, Liepins Edgars, Donets Pawel, Espina Laura, Farley Alistair J M, Shubin Kirill, Campillos Gonzalo Gomez, Kiuru Paula, Shishodia Shifali, Krahn Daniel, Leśniak Robert K, Schmidt Adrian Juliane, Calvopiña Karina, Turrientes María-Carmen, Kavanagh Madeline E, Lubriks Dmitrijs, Hinchliffe Philip, Langley Gareth W, Aboklaish Ali F, Eneroth Anders, Backlund Maria, Baran Andrei G, Nielsen Elisabet I, Speake Michael, Kuka Janis, Robinson John, Grinberga Solveiga, Robinson Lindsay, McDonough Michael A, Rydzik Anna M, Leissing Thomas M, Jimenez-Castellanos Juan Carlos, Avison Matthew B, Da Silva Pinto Solange, Pannifer Andrew D, Martjuga Marina, Widlake Emma, Priede Martins, Hopkins Navratilova Iva, Gniadkowski Marek, Belfrage Anna Karin, Brandt Peter, Yli-Kauhaluoma Jari, Bacque Eric, Page Malcolm G P, Björkling Fredrik, Tyrrell Jonathan M, Spencer James, Lang Pauline A, Baranczewski Pawel, Cantón Rafael, McElroy Stuart P, Jones Philip S, Baquero Fernando, Suna Edgars, Morrison Angus, Walsh Timothy R, Schofield Christopher J

СтатьяПоддержка NIH: внешняя программаПеревод пока не подготовлен

Аннотация

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.

Для цитирования: Brem Jürgen, Panduwawala Tharindi, Hansen Jon Ulf, Hewitt Joanne, Liepins Edgars, Donets Pawel, Espina Laura, Farley Alistair J M, Shubin Kirill, Campillos Gonzalo Gomez, Kiuru Paula, Shishodia Shifali, Krahn Daniel, Leśniak Robert K, Schmidt Adrian Juliane, Calvopiña Karina, Turrientes María-Carmen, Kavanagh Madeline E, Lubriks Dmitrijs, Hinchliffe Philip, Langley Gareth W, Aboklaish Ali F, Eneroth Anders, Backlund Maria, Baran Andrei G, Nielsen Elisabet I, Speake Michael, Kuka Janis, Robinson John, Grinberga Solveiga, Robinson Lindsay, McDonough Michael A, Rydzik Anna M, Leissing Thomas M, Jimenez-Castellanos Juan Carlos, Avison Matthew B, Da Silva Pinto Solange, Pannifer Andrew D, Martjuga Marina, Widlake Emma, Priede Martins, Hopkins Navratilova Iva, Gniadkowski Marek, Belfrage Anna Karin, Brandt Peter, Yli-Kauhaluoma Jari, Bacque Eric, Page Malcolm G P, Björkling Fredrik, Tyrrell Jonathan M, Spencer James, Lang Pauline A, Baranczewski Pawel, Cantón Rafael, McElroy Stuart P, Jones Philip S, Baquero Fernando, Suna Edgars, Morrison Angus, Walsh Timothy R, Schofield Christopher J. Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors.. Nature chemistry. 2021. DOI: 10.1038/s41557-021-00831-x.

Предметные рубрики MeSH

AnimalsGram-Negative BacteriaHumansMiceMicrobial Sensitivity TestsProtein BindingStructure-Activity Relationshipbeta-Lactamase Inhibitorsbeta-Lactams
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