In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 1−1
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ANTIMICROBIAL AGENTS: TARGETING PHOTODYNAMIC ANTIMICROBIAL CHEMOTHERAPY Photodynamic antimicrobial chemotherapy, in which light is used to activate a photosensitizer (PS) to generate cytotoxic oxidants from 3O2, suffers from the drawback of designing specificity for bacterial membranes while sparing host cells. In the present issue, Sol et al. (DOI: 10.1021/acsmedchemlett.7b00360) covalently incorporate a PS to a derivative of polymyxin B, an antibiotic that binds to lipid A in Gram-negative bacterial membranes. By replacing the diaminobutyric acid (DAB) residues of polymyxin B with lysine, intrinsic antibacterial activity is attenuated by ≥10-fold, a modification designed to reduce the potential for the emergence of resistance, but binding affinity for bacterial membranes is preserved. The hybrid molecule maintains the bactericidal effects of the DAB-based analogue under photochemical irradiation but, unlike the prototype, is essentially inactive in the dark. Binding studies indicate reduced association of the modified polymyxin B with normal dermal human fibroblasts, but the compound does exhibit light-mediated antibacterial activity toward Grampositive S. Aureus bacteria, which are devoid of lipid A. This provides an avenue for further study to define the membraneassociating properties.
assay to exhibit Ki values of 0.72 and 1 μM. In antibacterial assays using a clinical E. coli strain expressing NDM-1 and a recombinant strain engineered to overproduce the enzyme, these compounds interacted synergically with the NDM-1susceptible Meropenem to reduce the MIC value of the carbapenem by 8- to 16-fold. The two 4H-1,2,4-triazole-3-thiol derivatives offer potential for structural optimization into more potent and effective NDM-1 inhibitors.
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GLUCOSE LOWERING THERAPEUTIC: PAN-ACTIVATOR OF 5′-ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE 5′-Adenosine monophosphate-activated protein kinase (AMPK), a heterotrimeric serine/threonine kinase, is the primary regulator of energy homeostasis in eukaryotic cells and is believed to modulate the beneficial effects of exercise and weight loss in type 2 diabetes mellitus patients. In this issue, Sebhat et al. (doi: 10.1021/acsmedchemlett.7b00417) demonstrate that activation of AMPK in skeletal muscle is of importance for glucose lowering after optimization of a fragment-like screening lead into a series of compounds with different tissue distributions. This study culminated in the identification of MK8722 as a potent, systemically available pan-activator of AMPK that lowered both lipid and glucose levels in vivo. A key design element in the identification of MK-8722 was the replacement of a carboxylic acid-containing element in liver-selective compounds, with 1,4:3,6-dianhydro-D-mannitol, a polar heterocycle introduced to reduce transporter-mediated liver uptake. MK8722 appears to be a promising molecule with a unique profile for the treatment of diabetes and future studies may focus on understanding a reversible cardiac hypertrophy reminiscent of that seen in elite athletes that was observed in animal studies.
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ANTIMICROBIAL AGENTS: NEW DELHI METALLO-β-LACTAMASE-1 INHIBITORS The emergence of extended spectrum β-lactamases in Grampositive and Gram-negative bacteria compromises the efficacy of β-lactam-based antibiotics. The New Delhi metallo-β-lactamase1 (NDM-1), a dizinc-based enzyme, is of particular concern because of its clinical relevance and substrate promiscuity. Tondi et al. (DOI: 10.1021/acsmedchemlett.7b00428) have exploited a virtual screening approach to interrogate a library of ∼300,000 commercially available compounds. Two structurally related compounds that incorporate a 4H-1,2,4-triazole-3-thiol core, which is able to coordinate to both zinc ions present in the active site of NDM-1, were identified upon testing in an enzymatic © 2018 American Chemical Society
Published: January 11, 2018 1
DOI: 10.1021/acsmedchemlett.7b00536 ACS Med. Chem. Lett. 2018, 9, 1−1
