All cells must accomplish certain metabolic tasks to grow and divide. All cells, whether bacterial or human, accomplish these metabolic tasks by similar pathways. There are, however, some important differences that set bacteria apart metabolically from eukaryotic cells, and these differences can often be exploited in the development of antibacterial therapies.

A. Characteristics of bacterial growth

If bacterial cells are suspended in a liquid nutrient medium, the increase in cell number or mass can be measured in several ways. Techniques include microscopically counting the cells in a given volume using a ruled slide, counting the number of appropriately diluted cells that are able to form colonies following transfer to a solid nutrient (agar) surface, or quantitating the turbidity—which is proportional to the cell mass—of a culture in liquid medium.

 1. Stages of the bacterial growth cycle: Because bacteria reproduce by binary fission (one becomes two, two become four, four become eight, etc.), the number of cells increases exponentially with time (the exponential, or log, phase of growth). Depending on the species, the minimum doubling time can be as short as 10 minutes or as long as several days. For example, for a rapidly growing species such as Escherichia coli in a nutritionally complete medium, a single cell can give rise to some 10 million cells in just 8 hours. Eventually, growth slows and ceases entirely (stationary phase) as nutrients are depleted, and toxic waste products accumulate. Most cells in a stationary phase are not dead, however. If they are diluted into fresh growth medium, exponential growth will resume after a lag phase. The phases of the growth cycle are illustrated in Figure 1.

Fig1. Kinetics of bacterial growth in liquid medium.

 2. Surface growth: If a single bacterial cell is placed on a solid nutrient agar surface, the progeny of this cell remain close to the site of deposition and eventually form a compact macroscopic mass of cells called a colony (Figure 2). For rapidly growing species, overnight incubation at 30oC to 37oC is sufficient to produce visible colonies, each containing millions of cells. The gross characteristics of colonies (for example, color, shape, adherence, smell, and surface texture) can be useful guides for identification of the species of bacterium. Some species do not form compact circular colonies because the cells are capable of movement and swarm over the agar surface, especially if the surface is moist. Other species, particularly the actinomycetes, grow as long filaments of cells (mycelial growth).

Fig2. Growth of bacterial colonies on a solid, nutrient surface, for example, nutrient agar. [Note: The doubling time of bacteria is assumed to be 0.5 hr. in this example]

B. Energy production

 A distinctive feature of bacterial metabolism is the variety of mechanisms used to generate energy from carbon sources. Depending on the biochemical mechanism used, bacterial metabolism can be categorized into three types: aerobic respiration, anaerobic respiration, and fermentation (Figure 3).

Fig3. Overview of respiration, fermentation, and energy production in bacteria. [Note: Compounds other than oxygen, such as nitrate and sulfate, can be used as terminal electron acceptors in anaerobic respiration.]

1. Aerobic respiration is the metabolic process in which molecular oxygen serves as the terminal electron acceptor of the electron transport chain. In this process, oxygen is reduced to water. Respiration is the energy-generating mode used by all aerobic bacteria.

2. Anaerobic respiration is the metabolic process in which inorganic compounds other than molecular oxygen serve as the terminal electron acceptors. Depending on the species, acceptors can be molecules such as nitrate or sulfate. Anaerobic respiration can be used as an alternative to aerobic respiration in some species (facultative organisms), but is obligatory in other species (some obligate anaerobes). [Note: Other obligate anaerobes use fermentation as the main mode of energy metabolism. This is particularly true among the anaerobic bacteria of medical importance.]

3. Fermentation is an anaerobic process utilized by some bacterial species. It is the metabolic process by which an organic metabolic intermediate derived from a “fermentable” substrate serves as the final electron acceptor. The substrates that can be fermented and the final endproducts depend on the species. Regardless of the bacterium and the fermentation pathway, several unifying concepts are common to fermentation. By comparison to aerobic and anaerobic respiration, fermentation yields very little energy. The purpose of fermentation is to recycle nicotinamide adenine dinucleotide hydrogen (NADH) back to NAD. The reducing power that can be converted to energy via respiration is unrealized. The terminal electron acceptor in fermentation is pyruvate or a pyruvate derivative. Beyond these commonalities, the pathways and end products of fermentation are incredibly varied. These endproducts can be measured and are sometimes diagnostic for a given species. In addition, some fermentation endproducts can result in host toxicity and tissue damage.

C. Peptidoglycan synthesis

The bacterial peptidoglycan polymer is constructed on the surface of the cell membrane and is composed of a repeating carbohydrate backbone subunit, which is NAG–NAM . These backbone chains are cross-linked by short peptides (PEP) to form a rigid meshwork (Figure 4). Peptidoglycan biosynthesis occurs via the following series of steps.

Fig4. Synthesis of a bacterial cell wall.

 1. Activation of carbohydrate subunits: As in all biologic polymerizations, NAM and NAG subunits are activated by attachment to a carrier molecule, which in this case is the nucleotide uridine diphosphate (UDP).

 2. Synthesis of the linking peptide: A pentapeptide is added to UDP–NAM by sequential transfer of amino acids, with the two terminal alanine residues added as a dipeptide. This pentapeptide may contain some nonstandard amino acids, including, for example, diaminopimelic acid ([DAP] a metabolic precursor of lysine), and D-amino acids. The sequence of the pentapeptide is not dictated by an RNA template, but rather the specificity of the enzymes that form the peptide bonds.

 3. Transfer of the peptidoglycan unit to bactoprenol phosphate: The NAM–PEP moiety is transferred from the UDP carrier to another carrier, bactoprenol phosphate (BPP), located on the inner surface of the cell membrane. At this point, UDP–NAG transfers NAG to NAM–PEP, completing the peptidoglycan repeat unit, NAG–NAM–PEP, which is now attached to the carrier BPP.

4. Addition of the repeat unit to the existing peptidoglycan: BPP carries the NAG–NAM–PEP repeat unit through the cell mem brane to the outside surface where the peptidoglycan of the existing cell wall is located. The repeat unit is added to a free end of the existing peptidoglycan, increasing the length of the polymer by one repeat unit. Presumably, free ends are created by a limited hydrolytic loosening of the preexisting peptidoglycan.

 5. Cross-linking of the pentapeptide to the peptidoglycan back bone: Although the N–terminal end of the pentapeptide is attached to the NAM moieties of the backbone, the C–terminal end is dangling free. Cross-linking is brought about by a transpeptidation reaction that bonds DAP of the peptide in one chain to the alanine (ala) at position four of the peptide in an adjacent chain, causing the release of the terminal ala. This mode of direct cross linking is characteristic of E. coli and many other gram-negative species. By contrast, in gram-positive bacteria, such as Staphylococcus aureus, a glycine pentapeptide is usually interposed between the lysine (lys) at position three of one PEP and the ala at position four of the PEP to which the linkage is to be made (Figure 5).

Fig5. A. Glycine bridge in the peptidoglycan of Staphylococcus aureus. B. Organization of peptidoglycan layer in gram-positive cells.

 6. Peptidoglycan biosynthesis as a target of some antibacterial agents: Because many of the reactions involved in the synthesis of peptidoglycan are unique to bacteria, cell wall synthesis is an ideal target for some highly specific antibacterial agents, particularly the β-lactam antibiotics.

 a. β-Lactam antibiotics:

 Penicillins and cephalosporins inhibit the enzymes that catalyze transpeptidation and carboxypeptidation reactions of cell wall assembly. These enzymes are called penicillin-binding proteins (PBPs) because they all have active sites that bind β-lactam antibiotics. No single PBP species is the target of β-lactam antibiotics. Rather, their lethal effect on bacteria is the result of inactivation of multiple species of PBPs. Most PBPs are involved in bacterial cell wall synthesis. Acquired resistance to β-lactam antibiotics may result from genetic modifications that result in production of new PBPs that have a lower affinity for β-lactam antibiotics .

 b. Bacitracin, cycloserine, and vancomycin:

 Other antibiotics that interfere with peptidoglycan synthesis include bacitracin, which inhibits the recycling of bactoprenol phosphate; cycloserine, which inhibits synthesis of the D–ala–D–ala dipeptide that provides the two terminal residues of the pentapeptide; and vancomycin, which blocks incorporation of the NAG–NAM–PEP repeat unit into the growing peptidoglycan chain (see Figure 4). Because vancomycin binds to the terminat D-ala-D-ala dipeptide, this antibacterial agent also pre vents transpeptidation.

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