As a growing number of clinical isolates of are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of are synthesized by nonclassical transpeptidases, namely, the l,d-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of β-lactams determines their activity against Here, we studied the interactions of β-lactams with two l,d-transpeptidases in, namely, Ldt and Ldt, and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pansusceptible and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment of Finally, we solved the first crystal structure of an l,d-transpeptidase, Ldt, and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against .

␤-Lactams are the most widely used antibacterials. Among ␤-lactams, carbapenems are considered the last line of defense against recalcitrant infections. As recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before Mycobacterium tuberculosis strains resistant to these drugs will emerge. In the present study, we investigated the genetic basis that confers such resistance. To our surprise, instead of mutations in the known ␤-lactam targets, a single nucleotide polymorphism in the Rv2421c-Rv2422 intergenic region was common among M. tuberculosis mutants selected with meropenem or biapenem. We present data supporting the hypothesis that this locus harbors a previously unidentified gene that encodes a protein. This protein binds to ␤-lactams, slowly hydrolyzes the chromogenic ␤-lactam nitrocefin, and is inhibited by select penicillins and carbapenems and the ␤-lactamase inhibitor clavulanate. The mutation results in a W62R substitution that reduces the protein's nitrocefin-hydrolyzing activity and binding affinities for carbapenems.

KEYWORDSA recent report suggests that global incidence of Mycobacterium avium infections is significant and underestimated [1]. In immune-compromised hosts, for instance, patients infected with HIV, M. avium can cause chronic-disseminated disease with significant morbidity and mortality [2]. M. avium infections are difficult to treat as this pathogen is naturally resistant to most antibacterials available today. Therefore, new insights into vulnerabilities of this pathogen, that may be exploited to develop effective therapies, can have an immediate and a lasting impact.Mycobacteria possess a large cell wall that accounts for approximately 40% of cell's dry mass [3]. As a major component of the cell wall, the peptidoglycan serves as an anchor to vital cell wall molecules via covalent linkage to arabinogalactan layer to which mycolic acids are associated [4]. Until recently, it was widely accepted that D,D-transpeptidases (commonly known as penicillin-binding proteins) catalyzed the final step of peptidoglycan biosynthesis by linking the fourth amino acid of one stem peptide to the third amino acid of another thereby generating a 4→3 linked 3D-exoskeleton. However, the peptidoglycan of Mycobacterium tuberculosis, Mycobacterium abscessus and Mycobacterium smegmatis are predominantly cross-linked with 3→3 linkages generated by non-classical transpeptidases, namely L,D-transpeptidases [5][6][7][8][9]. Unlike D,D-transpeptidases that use serine to catalyze transpeptidation reaction, the catalytic residue in L,D-transpeptidases is cysteine which when mutated to serine completely abrogates its

Tuberculosis (TB) is the second most deadly infectious disease, caused mainly by M. tuberculosis in humans, usually affecting the lungs; it also attacks other parts of the body. The design of novel antibiotics attempts to overcome drug resistance, to shorten the treatment course, and to reduce drug interactions with antiretroviral therapies. Overcoming technological drawbacks of these therapeutic agents as well as improving the effectiveness of the drugs by targeting the infection reservoirs remain the central aims of pharmaceutical technology. In this framework, colloidal carriers appear as one of the most promising approaches for the development of more effective and compliant medicines by releasing the drugs slowly over prolonged time periods and reducing the current costs of treatment. Due to unique physicochemical properties (ultrasmall and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure) of colloidal carriers, they can facilitate the administration of antitubercular drugs, thereby overcoming some of the limitations in traditional antitubercular therapeutics. In recent years, encapsulation of antitubercular drugs in colloidal carrier systems is emerging as an innovative and promising alternative with enhanced therapeutic effectiveness and reduced undesirable side effects of the encapsulated drugs. The present review aims to describe the current conventional as well as combination drug therapy with special consideration towards the emerging role of novel colloidal carriers designed and targeted against TB. Colloidal carriers employing drugs alone or in combination targeted towards the site of action could lead to reduction in duration of conventional treatment, higher patient fulfillment, and prevention of antitubercular drug resistance or toxicity.

Mycobacteroides abscessus can cause chronic pulmonary infections requiring administration of multiple antibiotics, still resulting in a low cure rate. The incidence of M. abscessus disease is increasing in the United States and the developed regions of the world. We show for the first time that a protein, Glby, affects growth of this bacterium. Using a mouse model of lung M. abscessus disease, we demonstrate that Glby is required for this bacterium to cause disease.