The cell wall of Gram-negative bacteria has a very distinctive layered look under the electron microscope and is dramatically different from the Gram-positive cell wall. The inner layer consists of a thin peptidoglycan layer; the outer layer or outer membrane is a protein containing bilayer. The inner component of the outer membrane consists of lipids and the outer layer is composed of macromolecules known as lipopolysaccharide (LPS) or endotoxin. The LPS layer serves as a lipid barrier to water-soluble molecules, preventing their passage into the periplasmic space. Water-filled channels known as "porin channels" are located at regular intervals in the outer membrane. These porin channels allow certain ions and molecules, including antimicrobial agents, to pass through the outer membrane. One of the major mechanisms of resistance in Gram-negative bacteria is the inability of an antibiotic to pass through either the LPS layer or via the porin channels. If antimicrobial agents cannot gain entrance into the Gram-negative cell then the target sites for these agents cannot be accessed and resistance is seen. Based on the chemical structure of the molecule, some antimicrobial agents can pass via the porin channels and some cannot. For example, the chemical structure and ionic charge on penicillin G allows the drug to pass through the porin channels of Neisseria species but it cannot pass through the porin channels of most other Gram-negative bacteria, thus limiting its Gram-negative spectrum. Adding an amino group to the penicillin molecule creates ampicillin, which dramatically expands the spectrum of activity to include many Gram-negative bacteria by virtue of better porin channel penetration.

Other factors that contribute to pathogenicity include production of a wide array of exotoxins and enzymes that cause many different specific and nonspecific signs and symptoms harmful to the host. For example, enterohemorrhagic Escherichia coli (0157:H57) produces several potent exotoxins known as shigalike toxins that are absorbed into the bloodstream and cause organ-specific damage including the hemolytic - uremic syndrome. In contrast, the urinary pathogen Proteus mirabilis produces no exotoxins but produces an enzyme known as urease. Urease splits urea to form ammonium hydroxide which creates an alkaline urine, thus neutralizing the acid-

From: Management of Antimicrobials in Infectious Diseases Edited by: A. G. Mainous III and C. Pomeroy © Humana Press Inc., Totowa, NJ

Table 1

Examples of Intrinsic (Natural) Resistance to Selected Antimicrobial Agents

Bacteria Antimicrobial Agent Mechanism

Escherichia coli Penicillin Cannot penetrate the porin channels to gain entrance into the bacterial cell

Gram-negative bacteria Vancomycin Cannot penetrate the porin channels to gain entrance into the bacterial cell

Pseudomonas aeruginosa Imipenem and meropenem Specific porin channels missing that are required for drug penetration ity that inhibits the growth of many other bacteria. In addition, the alkaline urine can facilitate urolithiasis when magnesium ammonium phosphate salts precipitate out because these salts are less soluble in the more alkaline urine. Gram-negative bacteria virulence can also be mediated via adhesion factors, capsule formation, and the presence of flagella that provide antigenic variation and mobility.

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