Bacterial wall as target for attack: past, present, and future research

Abstract

When Bacteria, Archaea, and Eucarya separated from each other, a great deal of evolution had taken place. Only then did extensive diversity arise. The bacteria split off with the new property that they had a sacculus that protected them from their own turgor pressure. The saccular wall of murein (or peptidoglycan) was an effective solution to the osmotic pressure problem, but it then was a target for other life-forms, which created lysoymes and beta-lactams. The beta-lactams, with their four-member strained rings, are effective agents in nature and became the first antibiotic in human medicine. But that is by no means the end of the story. Over evolutionary time, bacteria challenged by beta-lactams evolved countermeasures such as beta-lactamases, and the producing organisms evolved variant beta-lactams. The biology of both classes became evident as the pharmaceutical industry isolated, modified, and produced new chemotherapeutic agents and as the properties of beta-lactams and beta-lactamases were examined by molecular techniques. This review attempts to fit the wall biology of current microbes and their clinical context into the way organisms developed on this planet as well as the changes arising since the work done by Fleming. It also outlines the scientific advances in our understanding of this broad area of biology.

FIG. 1.

The unit structure for bacterial wall formation. Shown is the disaccharide pentamuropeptide as a stretched molecule. This exact sequence is present in both E. coli and B. subtilis. By attachment to the carrier, bactoprenol, it is passed through the cytoplasmic membrane. It is then inserted in the cell wall. (Reprinted from reference 40 with permission from the publisher.)

FIG. 2.

The tetrasaccharide nonamuropeptide (the peptide portion is also known as the pentatetra peptide [5 plus 4 amino acids]). This is the cross-bridge that makes possible the formation of a fabric to cover the cell. (Reprinted from reference 40 with permission from the publisher.)

FIG. 3.

The part of the tetrasaccharide nonamuropeptide where the tail-to-tail linkages have been made between two muropeptides. The ionic interaction of the d-Ala-d-Ala and the diaminopimelic acid groups that are not involved in amide (peptide) formation is shown. This aspect of structure is essential for the “stressed nonamuropeptide” model.

FIG. 4.

Inertness of the poles in a growing E. coli cell. The old poles are shown in dark shading, and the new murein synthesized in the last generation is shown in white. Data from reference 12, but shown as examined by the NIH-Image software (13).

FIG. 5.

Structure of a unit of surface area of the sacculus of E. coli and B. subtillis. While the structure of the tessera is correct, the rectilinear arrangement, although typical of the presentation in textbooks, is certainly wrong. It would be correct if a murein fabric had been synthesized under stress-free conditions in the absence of the organisms. However, since the forces acting on the sacculus when it is an integral part of a functioning wall surface protecting the cell would stress it in six directions, it would become distorted to become hexagonal (see Fig. 6).

FIG. 6.

Tessera structure of a unit of cell surface in a growing bacterium. The chemical groups are the same as Fig. 5, but because of the turgor stresses in the wall, the fabric would be distorted into something that more closely resembles a hexagon.

FIG. 7.

Two classes of cell pressure responses in cells treated with ampicillin. Ancylobacter aquaticus cells were examined in a light-scattering apparatus exposed to a range of pressures that at some point crushed their gas-filled vesicles. Without ampicillin treatment, the collapse curve was monophasic like that marked “with sucrose” but required a higher pressure for collapse. After 20 min of treatment, the curve changed to the one marked “without sucrose.” This shows two branches, one higher and one lower than the original curve. The conclusion to be drawn is that different cells in the population exhibited different behaviors. Most of the cells ruptured, and the gas vesicles were exposed to the growth medium and were no longer compressed by the cell's turgor pressure. A smaller number of cells apparently stopped growing and acquired a higher turgor pressure. These cells were immune to the action of the antibiotic because the wall was not growing. (Modified from reference 47.)

FIG. 8.

Phylogenetic tree of MRSA strains. It shows the divergence of modern clinical strains from the original MRSA strain, which is shown on the top of the figure. It can be seen that from this original strain at least eight major strains (black circles) evolved and diverged but retained this MRSA character. The implication is that mecA arose only once, but variations on it arose much more often, probably in the current antibiotic era. (Reprinted from reference 14 with permission from the publisher.)