Mechanism of action
The antibacterial activity of rifamycins relies on the inhibition of bacterial DNA-dependent RNA synthesis. This is due to the high affinity of rifamycins for the  prokaryotic RNA polymerase. The selectivity of the rifamycins depends on the fact that they have a very poor affinity for  the analogous mammalian enzyme. Crystal structure data of the antibiotic bound to RNA polymerase indicates that rifamycin blocks synthesis by causing strong steric clashes with the growing oligonucleotide ("steric-occlusion" mechanism). If rifamycin binds the polymerase after the chain extension process has started, no inhibition is observed on the biosynthesis, consistent with a steric-occlusion mechanism. Single step high level resistance to the rifamycins occurs as the result of a single amino acid change in the bacterial DNA dependent RNA polymerase. Biosynthesis
The first information on the biosynthesis of the rifamycins came from studies using the stable isotope Carbon-13 and NMR spectroscopy to establish the origin of the carbon skeleton. These studies showed that the ansa chain was derived from acetate and propionate, in common with other polyketide antibiotics. The naphthalenic chromophore was shown to derive from a propionate unit coupled with a seven carbon amino moiety of unknown origin. The general scheme of biosynthesis starts with the uncommon starting unit, 3-amino-5-hydroxybenzoic acid (AHBA), via type I polyketide pathway (PKS I) in which chain extension is performed using 2 acetate and 8 propionate units. AHBA is believed to have originated from the Shikimate pathway, however this was not incorporated into the biosynthetic mechanism.
Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) are destroyed, thereby releasing free hemoglobin into the plasma. Excess hemoglobin is filtered by the kidneys, which excrete it into the urine, giving urine a purple color. Hemoglobinuria can lead to acute tubular necrosis which is an uncommon cause of a death of uni-traumatic patients recovering in the ICU. Causes
Acute glomerulonephritis
Burns
Renal cancer
Malaria
Paroxysmal nocturnal hemoglobinuria
Microangiopathies, e.g. hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) leading to microangiopathic hemolytic anemia
Transfusion reactions
IgM autoimmune hemolytic anemia
Glucose-6-phosphate dehydrogenase deficiency
Pyelonephritis
Sickle cell anemia
Tuberculosis of the urinary tract
March hemoglobinuria secondary to repetitive impacts on the body, usually the feet
Athletic nephritis secondary to strenuous exercise
Acute lead poisoning

Diagnosis
The diagnosis is often made based on the medical history, blood samples, and a urine sample. The absence of urine RBCs and RBC casts microscopically despite a positive dipstick test suggests hemoglobinuria or myoglobinuria. The medical term for RBCs in the urine is hematuria. See also
Hematuria

References


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