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Wherever thermodynamics allows, microbial life has evolved to transform and harness energy. Microbial life thus abounds in the most unexpected places, enabled by profound metabolic diversity. Within this diversity, energy is transformed primarily through variations on a few core mechanisms. Energy is further managed by the physiological processes of cell growth and maintenance that use energy. Some aspects of microbial physiology are streamlined for energetic efficiency while other aspects seem suboptimal or even wasteful. We propose that the energy that a microbe harnesses and devotes to growth and maintenance is a product of three broad tradeoffs: (i) economic, trading enzyme synthesis or operational cost for functional benefit, (ii) environmental, trading optimization for a single environment for adaptability to multiple environments, and (iii) thermodynamic, trading energetic yield for forward metabolic flux. Consideration of these tradeoffs allows one to reconcile features of microbial physiology that seem to opposingly promote either energetic efficiency or waste.

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).

In certain strictly anaerobic bacteria, the energy for growth is derived entirely from a decarboxylation reaction. A prominent example is Propionigenium modestum, which converts the free energy of the decarboxylation of (S)-methylmalonyl-CoA to propionyl-CoA (DeltaG degrees =-20.6 kJ/mol) into an electrochemical Na(+) ion gradient across the membrane. This energy source is used as a driving force for ATP synthesis by a Na(+)-translocating F(1)F(0) ATP synthase. According to bioenergetic considerations, approximately four decarboxylation events are necessary to support the synthesis of one ATP. This unique feature of using Na(+) instead of H(+) as the coupling ion has made this ATP synthase the paradigm to study the ion pathway across the membrane and its relationship to rotational catalysis. The membrane potential (Deltapsi) is the key driving force to convert ion translocation through the F(0) motor components into torque. The resulting rotation elicits conformational changes at the catalytic sites of the peripheral F(1) domain which are instrumental for ATP synthesis. Alkaliphilic bacteria also face the challenge of synthesizing ATP at a low electrochemical potential, but for entirely different reasons. Here, the low potential is not the result of insufficient energy input from substrate degradation, but of an inverse pH gradient. This is a consequence of the high environmental pH where these bacteria grow and the necessity to keep the intracellular pH in the neutral range. In spite of this unfavorable bioenergetic condition, ATP synthesis in alkaliphilic bacteria is coupled to the proton motive force (DeltamuH(+)) and not to the much higher sodium motive force (DeltamuNa(+)). A peculiar feature of the ATP synthases of alkaliphiles is the specific inhibition of their ATP hydrolysis activity. This inhibition appears to be an essential strategy for survival at high external pH: if the enzyme were to operate as an ATPase, protons would be pumped outwards to counteract the low DeltamuH(+), thus wasting valuable ATP and compromising acidification of the cytoplasm at alkaline pH.

Bacteria are the most remarkable organisms in the biosphere, surviving and growing in environments that support no other life forms. Underlying this ability is a flexible metabolism controlled by a multitude of environmental sensors and regulators of gene expression. It is not surprising, therefore, that bacterial respiration is complex and highly adaptable: virtually all bacteria have multiple, branched pathways for electron transfer from numerous low-potential reductants to several terminal electron acceptors. Such pathways, particularly those involved in anaerobic respiration, may involve periplasmic components, but the respiratory apparatus is largely membrane-bound and organized such that electron flow is coupled to proton (or sodium ion) transport, generating a protonmotive force. It has long been supposed that the multiplicity of pathways serves to provide flexibility in the face of environmental stresses, but the existence of apparently redundant pathways for electrons to a single acceptor, say dioxygen, is harder to explain. Clues have come from studying the expression of oxidases in response to growth conditions, the phenotypes of mutants lacking one or more oxidases, and biochemical characterization of individual oxidases. Terminal oxidases that share the essential properties of substrate (cytochrome c or quinol) oxidation, dioxygen reduction and, in some cases, proton translocation, differ in subunit architecture and complement of redox centres. Perhaps more significantly, they differ in their affinities for oxidant and reductant, mode of regulation, and inhibitor sensitivity; these differences to some extent rationalize the presence of multiple oxidases. However, intriguing requirements for particular functions in certain physiological functions remain unexplained. For example, a large body of evidence demonstrates that cytochrome bd is essential for growth and survival under certain conditions. In this review, the physiological basis of the many phenotypes of Cyd-mutants is explored, particularly the requirement for this oxidase in diazotrophy, growth at low protonmotive force, survival in the stationary phase, and resistance to oxidative stress and Fe(III) chelators.