Biochemical aspects of SCV formation- literature review

The phenotypic characteristics of SCVs can be related to defects in electron transport pathways. Defects in electron transport may affect the capacity of bacteria to produce ATP resulting in slow growth. Genetic mutations in hemB, menD, thyA and ctaA produce the SCV phenotype (Proctor et al. 2006). A mutation in hemB and ctaA blocks the biosynthesis of hemin, which is used in the cytochrome synthesis, whereas a mutation in menD blocks the synthesis of menadione, used in menaquinone synthesis. Since both menaquinone and cytochromes are components of the electron transport system, these mutations result in defective electron transport (Proctor et al. 2006). Similarly, a mutation in thyA, which encodes thymidylate synthase, results in impaired thymidine metabolism leading to SCV formation. Thus, the defects in electron transport are mainly responsible for the generation of SCVs.

The physiological characteristics of SCVs are mainly studied using hemB, menD  or thyA  mutants of S. aureus. All of these mutants show typical characteristics of SCVs such as slow growth, small colonies, decreased hemolytic and coagulase activity, reduced pigment formation and resistance to aminoglycosides. Complementing these mutants with hemB, menD or thyA respectively could restore the normal phenotype.

Defects in electron transport result in reduced carotenoid biosynthesis, which leads to reduced pigment formation by SCVs. Similarly, defects in electron transport decrease the amount of ATP used for cell-wall biosynthesis, leading to a slower growth rate and reduced membrane potential.  Reduction in the membrane potential results in the decreased uptake of cationic compounds including the aminoglycoside antibiotic (Proctor et al. 2006). The uptake of aminoglycosides depends on the membrane potential. Initiation of aminoglycoside uptake by bacteria requires a threshold level of membrane potential; above this level, the drug uptake is directly dependent on the magnitude of the membrane potential. Since SCVs show reduced membrane potential, uptake of aminoglycosides will be low, resulting in reduced killing by the antibiotic. Thus, SCVs can be selected by using aminoglycosides where the normal bacteria will be killed by the antibiotic wheras SCVs survive due to reduced uptake of the antibiotic. SCVs may be resistant to killing by other antibiotics such as penicillin, probably due to their slow growth rate.

Proctor et al. (2006). Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4(4), 295-305.