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更新于：2025-05-07

信号肽酶-II

更新于：2025-05-07

基本信息

别名-

简介-

关联

项与信号肽酶-II 相关的药物

G-0790

靶点

信号肽酶-II

作用机制

信号肽酶-II抑制剂

在研机构

Genentech, Inc.

原研机构

Genentech, Inc.

在研适应症

大肠杆菌感染

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

LspA inhibitor (Prokaryotics)

靶点

信号肽酶-II

作用机制

信号肽酶-II抑制剂

在研机构

Prokaryotics, Inc.

原研机构

Prokaryotics, Inc.

在研适应症

复杂的尿路感染

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与信号肽酶-II 相关的临床结果

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100 项与信号肽酶-II 相关的转化医学

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0 项与信号肽酶-II 相关的专利（医药）

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项与信号肽酶-II 相关的文献（医药）

2024-05-17·ACS Chemical Biology

Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase

Article

作者: Da Costa, Thaina M. ; Ballantine, Ross D. ; Ostrovitsa, Nikita ; Bowen, Katherine ; Geoghegan, Joan A. ; Cochrane, Stephen A. ; Bailey, Jonathan ; Levine, Paul M. ; Bann, Samantha J. ; Nolan, Mark D. ; Stewart, Lance J. ; Bhardwaj, Gaurav ; Scanlan, Eoin M. ; Weichert, Dietmar ; Caffrey, Martin ; Baker, David ; Olatunji, Samir ; Craven, Timothy W.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.

2024-01-01·Biochimica et Biophysica Acta (BBA) - Biomembranes

Liquid-chromatography mass spectrometry describes post-translational modification of Shewanella outer membrane proteins

Article

作者: Butt, Julea N ; Martins, Carlo ; Clarke, Thomas A ; Crack, Jason C ; van Wonderen, Jessica H ; Saalbach, Gerhard ; Edwards, Marcus J

Electrogenic bacteria deliver excess respiratory electrons to externally located metal oxide particles and electrodes. The biochemical basis for this process is arguably best understood for species of Shewanella where the integral membrane complex termed MtrCAB is key to electron transfer across the bacterial outer membranes. A crystal structure was recently resolved for MtrCAB from S. baltica OS185. However, X-ray diffraction did not resolve the N-terminal residues so that the lipidation status of proteins in the mature complex was poorly described. Here we report liquid chromatography mass spectrometry revealing the intact mass values for all three proteins in the MtrCAB complexes purified from Shewanella oneidensis MR-1 and S. baltica OS185. The masses of MtrA and MtrB are consistent with both proteins being processed by Signal Peptidase I and covalent attachment of ten c-type hemes to MtrA. The mass of MtrC is most reasonably interpreted as arising from protein processed by Signal Peptidase II to produce a diacylated lipoprotein containing ten c-type hemes. Our two-step protocol for liquid-chromatography mass spectrometry used a reverse phase column to achieve on-column detergent removal prior to gradient protein resolution and elution. We envisage the method will be capable of simultaneously resolving the intact mass values for multiple proteins in other membrane protein complexes.

2020-08-01·Microbiology4区 · 生物学

Role of the unique, non-essential phosphatidylglycerol::prolipoprotein diacylglyceryl transferase (Lgt) in Corynebacterium glutamicum

4区 · 生物学

Article

作者: Houssin, Christine ; Bayan, Nicolas ; Dietrich, Christiane ; Chami, Mohamed ; Argentini, Manuela ; Masi, Muriel ; Salmeron, Christophe ; Labarre, Cécile ; Cornu, David ; Sago, Laila ; Mohiman, Niloofar ; de Sousa d’Auria, Célia ; Dautin, Nathalie

Bacterial lipoproteins are secreted proteins that are post-translationally lipidated. Following synthesis, preprolipoproteins are transported through the cytoplasmic membrane via the Sec or Tat translocon. As they exit the transport machinery, they are recognized by a phosphatidylglycerol::prolipoprotein diacylglyceryl transferase (Lgt), which converts them to prolipoproteins by adding a diacylglyceryl group to the sulfhydryl side chain of the invariant Cys+1residue. Lipoprotein signal peptidase (LspA or signal peptidase II) subsequently cleaves the signal peptide, liberating the α-amino group of Cys+1, which can eventually be further modified. Here, we identified thelgtandlspAgenes from

Corynebacterium glutamicum

and found that they are unique but not essential. We found that Lgt is necessary for the acylation and membrane anchoring of two model lipoproteins expressed in this species: MusE, a

C. glutamicum

maltose-binding lipoprotein, and LppX, a

Mycobacterium tuberculosis

lipoprotein. However, Lgt is not required for these proteins’ signal peptide cleavage, or for LppX glycosylation. Taken together, these data show that in

C. glutamicum

the association of some lipoproteins with membranes through the covalent attachment of a lipid moiety is not essential for further post-translational modification.

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