ABSTRACT
Bacterial persistence coupled with biofilm formation is directly associated with failure of antibiotic treatment of tuberculosis. We have now identified 4-(4,7-DiMethyl-1,2,3,4-tetrahydroNaphthalene-1-yl)Pentanoic acid (DMNP), a synthetic diterpene analogue, as a lead compound that was capable of suppressing persistence and eradicating biofilms in Mycobacterium smegmatis. By using two reciprocal experimental approaches - ΔrelMsm and ΔrelZ gene knockout mutations versus relMsm and relZ overexpression technique - we showed that both RelMsm and RelZ (p)ppGpp synthetases are plausible candidates for serving as targets for DMNP. In vitro, DMNP inhibited (p)ppGpp-synthesizing activity of purified RelMsm in a concentration-dependent manner. These findings, supplemented by molecular docking simulation, suggest that DMNP targets the structural sites shared by RelMsm, RelZ, and presumably by a few others as yet unidentified (p)ppGpp producers, thereby inhibiting persister cell formation and eradicating biofilms. Therefore, DMNP may serve as a promising lead for development of antimycobacterial drugs.
Subject(s)
Bacterial Proteins/metabolism , Biofilms/drug effects , Diterpenes/pharmacology , Ligases/metabolism , Mycobacterium smegmatis/enzymology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Binding Sites , Diterpenes/chemistry , Diterpenes/metabolism , Ligases/antagonists & inhibitors , Microbial Sensitivity Tests , Molecular Docking Simulation , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/physiology , Protein Structure, TertiaryABSTRACT
Bipyridine N,N'-dioxide is a structural fragment found in many bioactive compounds. Furthermore, chiral analogues secured their place as powerful Lewis base catalysts. The scope of the existing methods for the synthesis of atropisomeric bipyridine N,N'-dioxides is limited. Herein, we present a practical, highly chemo- and stereoselective method for oxidative dimerization of chiral pyridine N-oxides using O2 as a terminal oxidant. A series of 13 axially chiral bipyridine N,N'-dioxides were synthesized in up to 75% yield.
ABSTRACT
A highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles has been developed that employs oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst. The reactions are usually complete in less than 10 min with only a 1 mol % catalyst loading. The reaction scope includes aromatic, heteroaromatic, and aliphatic amides, including derivatives of α-hydroxy and α-amino acids.
