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Chapter 3 : Microbial Pathogenic Factors: Small-Colony Variants

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Abstract:

A variant subpopulation of has been characterized that is defective in electron transport. These organisms grow slowly and are typical of the small-colony variants (SCVs), which were found to be defective in respiratory activity. Recent work has shown that most of the clinical isolates have inactive electron transport because of biosynthetic defects in the pathways leading to the synthesis of electron transport chain components. The changes in membrane potential and ATP also suggest that electron transport is decreased in both SCVs and adherent bacteria. SCVs from a variety of genera and species have most frequently been isolated from patients and animals treated with antibiotics, especially aminoglycosides, but also sulfonamides and β-lactam antibiotics. The host environment may favor the selection of staphylococcal SVCs. The basis for the persistent and antibiotic resistant infections may be related to the ability of SCVs to reside within cultured cells. Pigment formation and aminoglycoside transport require ATP and an intact electron transport system. The yellow carotenoid pigments that give SCV colonies their characteristic color require ATP for their biosynthesis. Menadione and hemin are the two most frequent substances that reverse the SCV phenotype. In addition, thiamine is a co-factor used in menadione biosynthesis and CO may be involved in the synthesis of the porphyrin ring found in hemin.

Citation: Proctor R. 2000. Microbial Pathogenic Factors: Small-Colony Variants, p 41-54. In Waldvogel F, Bisno A (ed), Infections Associated with Indwelling Medical Devices, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818067.ch3

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Electron Transport System
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Cell Wall Biosynthesis
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Transmission Electron Microscopy
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Figure 1

Clinical SCVs are often auxotrophic for menadione or hemin. These variants have defects in either menadione or hemin biosynthesis, making their electron transport chain inactive because they cannot synthesize menaquinone or the hemin portion of cytochromes. The organisms may also be auxotrophic for thiamine since this is a co-factor needed for menadione biosynthesis. Similarly, defects in cytochrome protein biosynthesis also give the SCV phenotype ( ). The F0F1 ATPase is a group of five proteins spanning the membrane that synthesizes ATP and creates an electrochemical gradient by using electrons transferred from the cytochromes. When large amounts of ATP are not available, cell wall biosynthesis slows, which results in small colonies. Decreases in the large electrochemical gradient cause reduced pigment biosynthesis and binding/transport of cationic compounds into staphylococci, leading to nonpigmented colonies that are more resistant to some antibiotics. Finally, interruption of electron transport is postulated to stimulate the production of negative regulators since SCVs show greatly decreased production of toxins. Therefore, interruption of electron transport can account for all of the phenotypic changes seen in SCVs.

Citation: Proctor R. 2000. Microbial Pathogenic Factors: Small-Colony Variants, p 41-54. In Waldvogel F, Bisno A (ed), Infections Associated with Indwelling Medical Devices, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818067.ch3
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Figure 2

Transmission electron micrograph of a menadione auxotrophic SCV, JB-1 (6). The organism was grown on tryptic soy broth, a low menadione-containing medium, and then incubated for 3.5 h at 35°C with bovine endothelial cells (6). Extracellular JB-1 cells were destroyed by addition of lysostaphin. After 18 h of further incubation, the endothelial monolayer was again treated with lysostaphin and washed and then prepared for transmission electron microscopy. Organisms with the endothelial cell are highlighted with arrows. Of note, the cellular architecture of the endothelial cell is very well preserved, as evidenced by intact mitochondria, philopodia, and other cytoplasmic structures, thus suggesting that the SCVs are causing minimal disruption to this mammalian cell.

Citation: Proctor R. 2000. Microbial Pathogenic Factors: Small-Colony Variants, p 41-54. In Waldvogel F, Bisno A (ed), Infections Associated with Indwelling Medical Devices, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818067.ch3
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Figure 3

(A) A hemin auxotrophic SCV, S. aureus PvL-3, is shown on the left side of this tryptic soy agar plate. This disc contains 1 µg of hemin/ml, which is sufficient to relieve the auxotrophy and allow the SCV to grow normally. The parent strain, 6850, is shown on the right half of the plate. The organisms were grown on tryptic soy agar and incubated for 36 h at 35°C. PvL-3 was selected by exposing the parent strain to 1 µg of gentamicin/ml for 3 days in tryptic soy broth (6). (B) A menadione auxotrophic SCV, JB-1, growing rapidly around a piece of filter paper that was supplemented with 1 µg of menadione/ml. In each case, the supplementation allows for rapid growth of the organism (large colonies that are pigmented).

Citation: Proctor R. 2000. Microbial Pathogenic Factors: Small-Colony Variants, p 41-54. In Waldvogel F, Bisno A (ed), Infections Associated with Indwelling Medical Devices, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818067.ch3
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Tables

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Table 1

Comparison of SCVs and adherent bacteria

Citation: Proctor R. 2000. Microbial Pathogenic Factors: Small-Colony Variants, p 41-54. In Waldvogel F, Bisno A (ed), Infections Associated with Indwelling Medical Devices, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818067.ch3

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