TY  - JOUR
AB  - Neocarzilin (NCA) is a natural product exhibiting potent antimigratory as well as antiproliferative effects. While vesicle amine transport protein 1 (VAT-1) was previously shown to inhibit migration upon NCA binding, the molecular mechanisms responsible for impaired proliferation remained elusive. We here introduce a chemical probe closely resembling the structural and stereochemical features of NCA and unravel bone marrow stromal antigen 2 (BST-2) as one of the targets responsible for the antiproliferative effect of NCA in cancer cells. The antiproliferative mechanism of NCA was confirmed in corresponding BST-2 knockout (KO) HeLa cells, which were less sensitive to compound treatment. Vice versa, reconstitution of BST-2 in the KO cells again reduced proliferation upon NCA addition, comparable to that of wild-type (wt) HeLa cells. Whole proteome mass spectrometric (MS) analysis of NCA-treated wt and KO cancer cells revealed regulated pathways and showed reduced levels of BST-2 upon NCA treatment. In-depth analysis of BST-2 levels in response to proteasome and lysosome inhibitors unraveled a lysosomal degradation path upon NCA treatment. As BST-2 mediates the release of epidermal growth factor receptor (EGFR) from lipid rafts to turn on proliferation signaling pathways, reduced BST-2 levels led to attenuated phosphorylation of STAT3. Furthermore, fluorescence microscopy confirmed increased colocalization of EGFR and lipid rafts in the presence of NCA. Overall, NCA represents a versatile anticancer natural product with a unique dual mode of action and unconventional inhibition of proliferation via BST-2 degradation.
AU  - Braun, J.*
AU  - Hu, Y.*
AU  - Jauch, A.T.*
AU  - Gronauer, T.F.
AU  - Mergner, J.*
AU  - Bach, N.C.*
AU  - Traube, F.R.*
AU  - Zahler, S.*
AU  - Sieber, S.A.*
C1  - 70712
C2  - 55561
CY  - 1155 16th St, Nw, Washington, Dc 20036 Usa
SP  - 1833-1840
TI  - Neocarzilin inhibits cancer cell proliferation via BST-2 degradation, resulting in lipid raft-trapped EGFR.
JO  - JACS Au
VL  - 4
IS  - 5
PB  - Amer Chemical Soc
PY  - 2024
SN  - 2691-3704
ER  - 

TY  - JOUR
AB  - Screening large molecule libraries against pathogenic bacteria is often challenged by a low hit rate due to limited uptake, underrepresentation of antibiotic structural motifs, and assays that do not resemble the infection conditions. To address these limitations, we present a screen of a focused library of alkyl guanidinium compounds, a structural motif associated with antibiotic activity and enhanced uptake, under host-mimicking infection conditions against a panel of disease-associated bacteria. Several hit molecules were identified with activities against Gram-positive and Gram-negative bacteria, highlighting the fidelity of the general concept. We selected one compound (L15) for in-depth mode of action studies that exhibited bactericidal activity against methicillin-resistant Staphylococcus aureus USA300 with a minimum inhibitory concentration of 1.5 μM. Structure-activity relationship studies confirmed the necessity of the guanidinium motif for antibiotic activity. The mode of action was investigated using affinity-based protein profiling with an L15 probe and identified the signal peptidase IB (SpsB) as the most promising hit. Validation by activity assays, binding site identification, docking, and molecular dynamics simulations demonstrated SpsB activation by L15, a recently described mechanism leading to the dysregulation of protein secretion and cell death. Overall, this study highlights the need for unconventional screening strategies to identify novel antibiotics.
AU  - Schum, D.*
AU  - Elsen, F.A.V.*
AU  - Ruddell, S.*
AU  - Schorpp, K.
AU  - Junca, H.*
AU  - Müsken, M.*
AU  - Chen, S.Y.*
AU  - Fiedler, M.K.*
AU  - Pickl, T.*
AU  - Pieper, D.H.*
AU  - Hadian, K.
AU  - Zacharias, M.*
AU  - Sieber, S.A.*
C1  - 71288
C2  - 55999
CY  - 1155 16th St, Nw, Washington, Dc 20036 Usa
SP  - 3125-3134
TI  - Screening privileged alkyl Guanidinium motifs under host-mimicking conditions reveals a novel antibiotic with an unconventional mode of action.
JO  - JACS Au
VL  - 4
IS  - 8
PB  - Amer Chemical Soc
PY  - 2024
SN  - 2691-3704
ER  -