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The Clinical Significance of Staphylococcus aureus Small Colony Variants

Klara C. Keim, Isaiah K. George, Landrye Reynolds and Allie Clinton Smith
American Society for Clinical Laboratory Science April 2023, DOI: https://doi.org/10.29074/ascls.2020002691

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Figures

  • Figure 1.
    Figure 1.

    Morphological differences exhibited by WT-SA and SA-SCV. Blood agar plates after 48 hours of incubation at 37ºC, showing a comparison of the colony morphology of (A) WT-SA to (B) SA-SCV phenotype. WT-SA with the normal phenotype, characterized by yellow pigmentation and hemolysis (A, SA Newman parental strain54). SA-SCV, characterized by pinpoint colonies that are nonpigmented and nonhemolytic (B, SA NewmanΔmenB55). Images taken by Klara C. Keim; strains provided by Catherine Wakeman, Texas Tech University Department of Biological Sciences.

  • Figure 2.
    Figure 2.

    Morphological and biochemical characteristics distinguishing WT-SA from SA-SCVs.

  • Figure 3.
    Figure 3.

    Illustration of the mechanisms leading to the SCV phenotype in SA and of their link to reduction in susceptibility to specific antibiotic classes. Double arrows refer to metabolites whose concentrations are reduced in the corresponding SCVs. Electron-transport–deficient SCVs show alterations in the pathways that lead to the synthesis of menadione or hemin (subsequent to mutations in biosynthetic enzymes), which cause a reduction in the amount of ATP produced. This leads to a reduced growth rate, which may affect the effectiveness of antibiotics active against dividing bacteria—such as cell-wall–active agents—and to a reduction in transmembrane potential, which impairs aminoglycoside uptake. Menadione-dependent SCVs are hypersusceptible to oxidant species, possibly because of reduced electron transport and alteration of the induction of antioxidant pathways (shown to be regulated by menaquinone in gram-negative bacteria). Thymidine-dependent SCVs are unable to convert deoxyuridine monophosphate to deoxythymidine monophosphate (dTMP) (using dihydrofolate [DHF] as a cofactor) because of mutations in thymidylate synthase, leading to dTMP depletion. These strains are nonsusceptible to antifolate agents that act on successive steps in this pathway, namely sulphonamides and diaminopyridines. Sulphonamides—such as SMX—are inhibitors of dihydropteroate (DHP) synthase that produce DHP from dihydropteridine pyrophosphate and para-aminobenzoic acid. Diaminopyridines—such as TMP—are inhibitors of DHF reductase, which catalyze the reduction of DHF to tetrahydrofolate. They also show a reduced growth rate. Globally, antibiotics may also be less bactericidal toward electron-transport–deficient SCVs because of a reduced production of reactive oxygen species. DHF, dihydrofolate; DHP, dihydropteroate; dTMP, deoxythymidine monophosphate; Haemin-dep, hemin dependent; Men-dep, menadione dependent; Thy-dep, thymidine dependent. Reprinted with permission from Garcia et al, 2013.24

  • Figure 4.
    Figure 4.

    Illustration of PA-induced SA-SCV selection. (Left) Colony size of SA under normal conditions. (Right) In the presence of respiratory toxins like HQNO or the Pseudomonas quinolone signal, pyocyanin or cyanide produced by PA leads to selection of the electron-transport–deficient SCV phenotype in SA. Reprinted with permission from Biswas et al, 2009.40

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The Clinical Significance of Staphylococcus aureus Small Colony Variants
Klara C. Keim, Isaiah K. George, Landrye Reynolds, Allie Clinton Smith
American Society for Clinical Laboratory Science Apr 2023, DOI: 10.29074/ascls.2020002691
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