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1.
ACS Chem Biol ; 19(5): 1106-1115, 2024 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-38602492

RESUMO

The prevalence of multidrug-resistant (MDR) pathogens combined with a decline in antibiotic discovery presents a major challenge for health care. To refill the discovery pipeline, we need to find new ways to uncover new chemical entities. Here, we report the global genome mining-guided discovery of new lipopeptide antibiotics tridecaptin A5 and tridecaptin D, which exhibit unusual bioactivities within their class. The change in the antibacterial spectrum of Oct-TriA5 was explained solely by a Phe to Trp substitution as compared to Oct-TriA1, while Oct-TriD contained 6 substitutions. Metabolomic analysis of producer Paenibacillus sp. JJ-21 validated the predicted amino acid sequence of tridecaptin A5. Screening of tridecaptin analogues substituted at position 9 identified Oct-His9 as a potent congener with exceptional efficacy against Pseudomonas aeruginosa and reduced hemolytic and cytotoxic properties. Our work highlights the promise of tridecaptin analogues to combat MDR pathogens.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Antibacterianos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Humanos , Especificidade de Hospedeiro , Descoberta de Drogas , Lipopeptídeos/farmacologia , Lipopeptídeos/química , Peptídeos
2.
J Med Chem ; 66(8): 6002-6009, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37071814

RESUMO

Brevicidine and laterocidine are macrocyclic lipodepsipeptides with selective activity against Gram-negative bacteria, including colistin-resistant strains. Previously, the macrocyclic core of these peptides was thought essential for antibacterial activity. In this study, we show that C-terminal amidation of linear brevicidine and laterocidine scaffolds, and substitution of the native Thr9, yields linear analogues that retain the potent antibacterial activity and low hemolysis of the parent compounds. Furthermore, an alanine scan of both peptides revealed that the aromatic and basic amino acids within the common central scaffold are essential for antibacterial activity. This linearization strategy for modification of cyclic peptides is a highly effective way to reduce the time and cost of peptide synthesis and may be applicable to other non-ribosomal antibacterial peptides.


Assuntos
Antibacterianos , Lipopeptídeos , Lipopeptídeos/química , Antibacterianos/química , Peptídeos Cíclicos/química , Bactérias Gram-Negativas , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana
3.
ACS Infect Dis ; 9(4): 739-748, 2023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-37000899

RESUMO

The unabated rise of antibiotic resistance has raised the specter of a post-antibiotic era and underscored the importance of developing new classes of antibiotics. The relacidines are a recently discovered group of nonribosomal lipopeptide antibiotics that show promising activity against Gram-negative pathogens and share structural similarities with brevicidine and laterocidine. While the first reports of the relacidines indicated that they possess a C-terminal five-amino acid macrolactone, an N-terminal lipid tail, and an overall positive charge, no stereochemical configuration was assigned, thereby precluding a full structure determination. To address this issue, we here report a bioinformatics guided total synthesis of relacidine A and B and show that the authentic natural products match our predicted and synthesized structures. Following on this, we also synthesized an analogue of relacidine A wherein the ester linkage of the macrolactone was replaced by the corresponding amide. This analogue was found to possess enhanced hydrolytic stability while maintaining the antibacterial activity of the natural product in both in vitro and in vivo efficacy studies.


Assuntos
Antibacterianos , Lipopeptídeos , Antibacterianos/química , Lipopeptídeos/farmacologia , Lipopeptídeos/química , Amidas
4.
RSC Med Chem ; 13(12): 1640-1643, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36545437

RESUMO

The brevicidine and laterocidine family of lipopeptide antibiotics exhibit strong activity against multidrug-resistant Gram-negative bacteria, while showing low propensity to induce resistance. Both peptides feature a branched lipid tail on the N-terminal residue, which for brevicidine is chiral. Here, we report the synthesis and biological evaluation of a library of brevicidine and laterocidine analogues wherein the N-terminal lipid is replaced with linear achiral fatty acids. Optimal lipid chain lengths were determined and new analogues with strong activity against colistin-resistant E. coli produced.

5.
Chem Sci ; 13(12): 3563-3570, 2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35432860

RESUMO

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models.

6.
J Med Chem ; 63(17): 9340-9359, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787138

RESUMO

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure-activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs.


Assuntos
Aciltransferases/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfolipases/antagonistas & inibidores , Aciltransferases/química , Células Hep G2 , Humanos , Modelos Moleculares , Fosfolipases/química , Conformação Proteica , Relação Estrutura-Atividade
7.
ACS Chem Biol ; 14(2): 164-169, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30620559

RESUMO

Phospholipase A2, group XVI (PLA2G16) is a thiol hydrolase from the HRASLS family that regulates lipolysis in adipose tissue and has been identified as a host factor enabling the cellular entry of picornaviruses. Chemical tools are essential to visualize and control PLA2G16 activity, but they have not been reported to date. Here, we show that MB064, which is a fluorescent lipase probe, also labels recombinant and endogenously expressed PLA2G16. Competitive activity-based protein profiling (ABPP) using MB064 enabled the discovery of α-ketoamides as the first selective PLA2G16 inhibitors. LEI110 was identified as a potent PLA2G16 inhibitor ( Ki = 20 nM) that reduces cellular arachidonic acid levels and oleic acid-induced lipolysis in human HepG2 cells. Gel-based ABPP and chemical proteomics showed that LEI110 is a selective pan-inhibitor of the HRASLS family of thiol hydrolases (i.e., PLA2G16, HRASLS2, RARRES3 and iNAT). Molecular dynamic simulations of LEI110 in the reported crystal structure of PLA2G16 provided insight in the potential ligand-protein interactions to explain its binding mode. In conclusion, we have developed the first selective inhibitor that can be used to study the cellular role of PLA2G16.


Assuntos
Amidas/química , Inibidores Enzimáticos/farmacologia , Fosfolipases A2/efeitos dos fármacos , Proteínas/química , Animais , Inibidores Enzimáticos/química , Humanos
8.
J Med Chem ; 57(14): 6197-209, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25006746

RESUMO

Mammalian genomes encode seven catalytic proteasome subunits, namely, ß1c, ß2c, ß5c (assembled into constitutive 20S proteasome core particles), ß1i, ß2i, ß5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit ß5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of ß1c/ß1i, ß2c/ß2i, or ß5c/ß5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable ß1i and ß5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency. These compounds are the result of a rational design strategy using known inhibitors as starting points and introducing structural features according to the X-ray structures of the murine constitutive and immunoproteasome 20S core particles.


Assuntos
Desenho de Fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Relação Estrutura-Atividade
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