Summary Understanding the basis of bacterial persistence in latent infections is critical for eradication of tuberculosis. Analysis of Mycobacterium tuberculosis mRNA expression in an in vitro model of non-replicating persistence indicated that the bacilli require electron transport chain components and ATP synthesis for survival. Additionally, low μM concentrations of aminoalkoxydiphenylmethane derivatives inhibited both the aerobic growth and survival of non-replicating, persistent M. tuberculosis. Metabolic labeling studies and quantitation of cellular menaquinone levels suggested that menaquinone synthesis, and consequently electron transport, is the target of the aminoalkoxydiphenylmethane derivatives. This hypothesis is strongly supported by the observations that treatment with these compounds inhibits oxygen consumption and that supplementation of growth medium with exogenous menaquinone rescued both growth and oxygen consumption of treated bacilli. In vitro assays indicate that the aminoalkoxydiphenylmethane derivatives specifically inhibit MenA, an enzyme involved in the synthesis of menaquinone. Thus, the results provide insight into the physiology of mycobacterial persistence and a basis for the development of novel drugs that enhance eradication of persistent bacilli and latent tuberculosis.

Weigh it out in air! The DABAL reagent (Me3Al)2⋅(DABCO) (DABCO=1,4‐diazabicyclo[2.2.2]octane) can be easily handled under normal laboratory conditions. Furthermore, chiral secondary alcohols can be efficiently prepared from prochiral aldehydes (see scheme; TOF=turnover frequency) by using either DABAL or AlR3 reagents (R=Me, Et). Thus, DABAL can be used as an efficient, convenient alternative to the Schumann–Blum reagent.

Since utilization of menaquinone in the electron transport system is a characteristic of Gram-positive organisms, the 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) inhibitors 1a and 2a act as selective antibacterial agents against organisms such as methicillin-resistant Stapylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE), and Mycobacterium spp. Growth of drug-resistant Gram-positive organisms was sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid new drug target in Gram-positive organisms.Antimicrobial resistance of pathogens is a global problem. Each year worldwide, more than 11 million people die from the major infectious killers (i.e., MDR a tuberculosis, malaria, HIV, diarrhea diseases, and pneumonia). 1 The increasing drug resistance among Gram-positive bacteria is a significant problem because they are responsible for one-third of nosocomial * To whom correspondence should be addressed. For M.K. : phone, 970-491-7628; fax, 970-491-1815; e-mail, michio.kurosu@colostate.edu. For D.C.C.: phone, 970-491-3308; fax, 970-491-1815; e-mail, dean The results of over 10 years of screening of strains and molecular targets (existing and new) from traditional product sources (randomly generated library molecules, secondary metabolites, and drug libraries) have been disappointing. 4 Therefore, identification of new molecular targets and mechanisms of action that involved identifying essential, ubiquitous bacterial genes in pathogens that are prokaryote and eukaryote selective to prevent side effects in the host has been studied.The lipid-soluble electron carriers (lipoquinones) occupy a central and essential role in electron transport coupled ATP synthesis. The lipoquinones involved in the respiratory chains of bacteria consist of menaquinones and ubiquinones. From the taxonomic studies it is evident that a majority of Gram-positive bacteria including Mycobacterium spp. utilize only menaquinone in their electron transport systems, 5 and menaquinone biosynthesis is essential for survival of nonfermenting Gram-positive bacteria. 6 On the other hand, Gram-negative organisms such as E. coli utilize ubiquinone (CoQ) under aerobic conditions and utilize menaquinone under anaerobic conditions. Moreover, the electron transport chain in humans does not utilize menaquinone. 7 Therefore, inhibitors of menaquinone biosynthesis have great potential for the development of novel and selective drugs against MDR Gram-positive pathogens. 8 However, no study on the development of inhibitors for menaquinone biosynthetic enzymes has been reported. In this communication, we report that inhibition of 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA), which catalyzes a formal decarboxylative prenylation of 1,4-dihydroxy-2-napthoate (DHNA) (Figure 1), 9 showed significant growth inhibitory activities against drug-resistant Gram-positive bacteria.The MenA activity was characterized using membrane fractions prepared from M. tuberculosis as previously described. 11 MenA is predicted to hav...

Arynes, generated from trimethylsilyl phenyltriflate precursors, have been found to react with thioureas via a formal π-insertion into the C═S bond. The reaction contrasts with that of ureas, which proceeds via benzyne σ-insertion into the C-N bond, and represents a new, operationally simple route to functionalized amidines.

Simple phosphoramidite ligands afford good to excellent levels of enantioselectivity in 1,4-additions of AlR3 species to enones; sequential carboalumination-ACA cascades are possible.