Sixteen desmuramyl analogs of muramyl dipeptide (MDP) were tested for their abilities to stimulate cytotoxic factor secretion by mouse peritoneal macrophages. Among them, the pseudohexapeptide Boc-Gly psi [CH2O]-D-Ala-Ala-D-Glu[Lys(H-Gly)NHEt]-NH2 appeared to be four times more effective than MDP. From this study, the D configuration of the pseudo-alanyl (or lactyl) residue appears to be essential for activity.
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J Med Chem
November 2024
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
Vancomycin and norvancomycin have diminished antibacterial efficacy due to acquired or intrinsic resistance from mutations in the terminal dipeptide of lipid II in Gram-positive bacteria or failure to penetrate into the periplasm in Gram-negative bacteria. Herein, we rationally designed and synthesized a series of vancomycin analogues bearing single amine or guanidine functionality, altering various linkers and modification sites, to combat the resistance. Extensive antibacterial screening was performed to delineate a comprehensive SAR.
View Article and Find Full Text PDFJ Chem Inf Model
October 2024
Department of Physics, Florida International University, Miami, Florida 33199, United States.
The lantibiotic pore-forming peptide nisin is a promising candidate in the fight against multidrug-resistant bacteria due to its unique structure, which allows it to disrupt bacteria in two distinct ways─Lipid II trafficking and transmembrane pore formation. However, exactly how nisin and Lipid II assemble into oligomeric pore structures in the bacterial membrane is not known. Spontaneous peptide assembly into pores is difficult to observe in even the very long-time scale molecular dynamics (MD) simulations.
View Article and Find Full Text PDFJ Am Chem Soc
September 2024
Institute for Pharmaceutical Microbiology, University of Bonn, University Hospital Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany.
The synthetic small molecule DCAP is a chemically well-characterized compound with antibiotic activity against Gram-positive and Gram-negative bacteria, including drug-resistant pathogens. Until now, its mechanism of action was proposed to rely exclusively on targeting the bacterial membrane, thereby causing membrane depolarization, and increasing membrane permeability (Eun 2012, 134 (28), 11322-11325; Hurley 2015, 6, 466-471). Here, we show that the antibiotic activity of DCAP results from a dual mode of action that is more targeted and multifaceted than previously anticipated.
View Article and Find Full Text PDFProtein Pept Lett
July 2024
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
Background: is a common pathogen with strains that are resistant to existing antibiotics. MurJ from (SaMurJ), an integral membrane protein functioning as Lipid II flippase, is a potential target for developing new antibacterial agents against this pathogen. Successful expression and purification of this protein shall be useful in the development of drugs against this target.
View Article and Find Full Text PDFOrg Biomol Chem
August 2024
University Center Varaždin, University North, HR-42000 Varaždin, Croatia.
Muramyl dipeptide (MDP) is the smallest essential peptidoglycan substructure capable of promoting both innate and adaptive immune responses. Herein, we report on the design, synthesis, and study of the adjuvant properties of two novel MDP analogs containing an achiral adamantyl moiety attached to the desmuramyl dipeptide (DMP) pharmacophore and additionally modified by one mannosyl subunit (derivative 7) or two mannosyl subunits (derivative 11). Mannose substructures were introduced in order to assess how the degree of mannosylation affects the immune response and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) binding affinity, compared to the reference compound ManAdDMP.
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