Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-l-glutamate/glutamine cell wall structure, and bacterial replication

New antibiotics to combat the emerging pandemic of drug-resistant strains of Mycobacterium tuberculosis are urgently needed. We have investigated the effects on M. tuberculosis of phosphorothioate-modified antisense oligodeoxyribonucleotides (PS-ODNs) against the mRNA of glutamine synthetase, an enzyme whose export is associated with pathogenicity and with the formation of a poly-l-glutamate/glutamine cell wall structure. Treatment of virulent M. tuberculosis with 10 μM antisense PS-ODNs reduced glutamine synthetase activity and expression by 25–50% depending on whether one, two, or three different PS-ODNs were used and the PS-ODNs' specific target sites on the mRNA. Treatment with PS-ODNs of a recombinant strain of Mycobacterium smegmatis expressing M. tuberculosis glutamine synthetase selectively inhibited the recombinant enzyme but not the endogenous enzyme for which the mRNA transcript was mismatched by 2–4 nt. Treatment of M. tuberculosis with the antisense PS-ODNs also reduced the amount of poly-l-glutamate/glutamine in the cell wall by 24%. Finally, treatment with antisense PS-ODNs reduced M. tuberculosis growth by 0.7 logs (1 PS-ODN) to 1.25 logs (3 PS-ODNs) but had no effect on the growth of M. smegmatis, which does not export glutamine synthetase nor possess the poly-l-glutamate/glutamine (P-l-glx) cell wall structure. The experiments indicate that the antisense PS-ODNs enter the cytoplasm of M. tuberculosis and bind to their cognate targets. Although more potent ODN technology is needed, this study demonstrates the feasibility of using antisense ODNs in the antibiotic armamentarium against M. tuberculosis.

A series of manuals of Gothic ornament.

Pt. 3 has imprint: London : J.H. and J. Parker.

Reports of cases relative to the duty and office of a justice of the peace, from Michaelmas term 1776, inclusive, to Trinity term 1785, inclusive.

"There were editions in 1786 and 1790, and a Dublin reprint ... in 1790. These contained only 388 pages. The 1800 edition has 593 pages, with table of principal matters. Some copies of the quarto with the earlier imprints appear also to have pages 389 to 593 added, and to be complete."--Soule, Lawyer's ref. manual, 1884.

Essai sur l'histoire de la musique des francs (e̲poque merovingienne)

Mode of access: Internet.

Ordonnances des roys de France de la troisième race, recueillies par ordre chronologique.

Index B: Table chronologique des ordonnances des rois de France de la troisième race jusqu'au règne de Louis XII inclusivement, suivie d'une table alphabétique pour en faciliter l'usage, par J. M. Pardessus ... . Paris, Imprimerie royale, 1847. 2 p. l., viii, 607 p. 40 cm.

Heinrich Laubes gesammelte Werke in fünfzig Bänden [microform] /

Each volume has also special t.p.

L'Amérique latine et la guerre europ��enne. Première partie.

At head of title: Groupement des universités et grandes écoles de France pour les relations avec l'Amérique latine.

Flore française destinée aux herborisations, ou Description des plantes croissant naturellement en France, ou cultivées pour l'usage de l'homme et des animaux, avec l'analyse des genres et leur tableau d'après le système de Linné ...

"Table générale et supplément final." (2 p. l., 189, [1] p.) issued in 1838.

Voyage autour du monde, et principalement a la côte nord-quest de l'Amérique, fait en 1785, 1786, 1787 et 1788 a bord du King-George et de la Queen-Charlotte, par les Capitaines Portlock et Dixon... /

Se trata de una serie de 37 cartas firmadas por "W.B." (William Bereford), supercargo del barco "Queen Charlotte", y editadas con una introducción de George Dixon. Se incluye dedicatoria a Joseph Banks.

Oeuvres inédites de J. de La Fontaine avec diverses pièces en vers et en prose qui lui ont été attribuées recuillies pour la première fois /

Mode of access: Internet.

Annales de l'imprimerie des Alde,

Engraved book plates reading. Friederici Nicolai et Amicorum.

L'Italia durante le preponderanze straniere; narrazione storica dal 1530 al 1789.

Added t.p.: L'Italia sotto l'aspetto fisico, storico, letterario, artistico, militare e statistico...

Zur Schleswig-Holsteinischen im August 1956.

With (by the same author): Zur Schleswig-Holsteinischen Sache im November 1858. Braunschweig, 1858. (58 p.) -- Die Verfassungsfrage in der Holsteinischen Ständeversammlung. Braunschweig, 1859. (42 p.) -- Ein Mahnruf an das deutsche Volk. Leipzig, 1860. (36 p.)

A glossary of terms used in Grecian, Roman, Italian, and Gothic architecture.

"The works chiefly made use of":p. [vii-viii].

The Library journal, chiefly devoted to library economy and bibliography.

Subtitle varies.