Physiology of Mycobacteria

Abstract

Mycobacterium tuberculosis is a prototrophic, metabolically flexible bacterium that has achieved a spread in the human population that is unmatched by any other bacterial pathogen. The success of M. tuberculosis as a pathogen can be attributed to its extraordinary stealth and capacity to adapt to environmental changes throughout the course of infection. These changes include: nutrient deprivation, hypoxia, various exogenous stress conditions and, in the case of the pathogenic species, the intraphagosomal environment. Knowledge of the physiology of M. tuberculosis during this process has been limited by the slow growth of the bacterium in the laboratory and other technical problems such as cell aggregation. Advances in genomics and molecular methods to analyse the M. tuberculosis genome have revealed that adaptive changes are mediated by complex regulatory networks and signals, resulting in temporal gene expression coupled to metabolic and energetic changes. An important goal for bacterial physiologists will be to elucidate the physiology of M. tuberculosis during the transition between the diverse conditions encountered by M. tuberculosis. This review covers the growth of the mycobacterial cell and how environmental stimuli are sensed by this bacterium. Adaptation to different environments is described from the viewpoint of nutrient acquisition, energy generation and regulation. To gain quantitative understanding of mycobacterial physiology will require a systems biology approach and recent efforts in this area are discussed. “It is now 100 years since the first mycobacterium was isolated by Hansen (1874). Somewhat ironically, this was the leprosy bacillus, Mycobacterium leprae, which even today is still resisting all attempts to cultivate it in the laboratory. The tubercle bacillus, M. tuberculosis was not discovered until eight years later (Koch, 1882) and this has remained an object of intensive investigation ever since. The widespread interest in the mycobacteria of course stems from the diseases they cause and, lest it be imagined that tuberculosis is a disease which has now been largely conquered and that leprosy is of relatively rare occurrence, current estimates for the number of case of tuberculosis and leprosy in the world today are 20,000,000 and 11,000,000, respectively (Bechelli and Dominguez, 1972). The annual estimated mortality rate is equally dramatic, namely 3,000,000 (World Health Organization, 1974). Also causing unease is the continuing isolation from tubercular patients of strains already resistant to one or more chemotherapeutic agent”. C. Ratledge (1976).

Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis

“…Nevertheless, the Mtb genome encodes five transporters implicated in sugar uptake. The LpqY-SugA-SugB-SugC ABC transporter was predicted to be of critical importance for virulence of Mtb, leading to the speculation that unidentified host sugars are also available to Mtb, at least early during infection (5,(12)(13)(14). Our studies, however, now convincingly show that this permease exhibits a high specificity for trehalose, a disaccharide not synthesized by mammals.…”

“…In particular, the LpqY-SugA-SugB-SugC ABC transporter was predicted to be critical for growth both in macrophages (12) and in mice during the acute infection phase (13). These findings were interpreted as indicating that, despite the prevalence of host lipids, as-yet-unidentified host sugars are also available to Mtb early during infection, and that metabolism of these sugars is crucial for pathogenesis (5,(12)(13)(14).Here we show, however, that the LpqY-SugA-SugB-SugC ABC transporter is highly specific for uptake of the disaccharide trehalose, a sugar not present in mammals, thus unlikely to be involved in nutrient acquisition from the host. In contrast, it is demonstrated that this importer plays a role in recycling of extracellular trehalose released from trehalose-containing molecules synthesized by the bacillus.…”

“…2C). To assess the substrate specificity, uptake competition assays were performed with 14 C-trehalose in the presence of an excess of unlabeled competing sugars. Except for the positive-control trehalose, no competition was observable using such structurally similar molecules as glucose, (Fig.…”

“…In particular, the LpqY-SugA-SugB-SugC ABC transporter was predicted to be critical for growth both in macrophages (12) and in mice during the acute infection phase (13). These findings were interpreted as indicating that, despite the prevalence of host lipids, as-yet-unidentified host sugars are also available to Mtb early during infection, and that metabolism of these sugars is crucial for pathogenesis (5,(12)(13)(14).…”

Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis

“…Characterization of such genes presents a daunting task. M. tuberculosis is thought to be subjected to a myriad of conditions during its life cycle in the host, such as low pH, reactive oxygen and nitrogen species, and so on (6,7). Understanding how M. tuberculosis adapts to and even thrives in such diverse environments is critical to our understanding of the pathology itself and for the discovery of novel therapeutics to treat tuberculosis.…”