Vitamin D Compounds Are Bactericidal against Streptococcus mutans and Target the Bacitracin-Associated Efflux System

Abstract

Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of in a high-throughput screen of FDA-approved drugs. Previous studies have demonstrated that certain derivatives of vitamin D possess lytic activity against other bacteria, though the mechanism has not yet been established. Through the use of a combinatorial approach, the vitamin D derivative doxercalciferol was shown to act synergistically with bacitracin, a polypeptide-type drug that is known to interfere with cell wall synthesis, suggesting that doxercalciferol may act in a bacitracin-related pathway. Innate resistance to bacitracin is attributed to efflux by a conserved ABC-type transporter, which in is encoded by the operon. possesses two characterized mechanisms of resistance to bacitracin, the ABC transporter, bacitracin resistance (Mbr) cassette, consisting of MbrABCD, and the rhamnose-glucose polysaccharide (Rgp) system, RgpABCDEFGHI. Loss of function of the transporter in and mutants exacerbated the effect of the combination of doxercalciferol and bacitracin. Despite conservation of a transporter homologous to, the combination of doxercalciferol and bacitracin appeared to be synergistic only in streptococcal species. We conclude that vitamin D derivatives possess lytic activity against and act through a mechanism dependent on the bacitracin resistance mechanism of MbrABCD.

Sirtuin-1 and Its Relevance in Vascular Calcification

“…The benefit of vitamin D in mineral metabolism and skeletal health is well-documented in the literature. In the endothelium, vitamin D modulates macrophage and T lymphocyte activity, and it exerts anti-inflammatory and antibacterial activities [126,127]. Vitamin D supplements show extensive benefits if the population has vitamin D deficiency [128][129][130][131][132].…”

A Drug Repositioning Approach Reveals that Streptococcus mutans Is Susceptible to a Diverse Range of Established Antimicrobials and Nonantibiotics

“…In addition to assigning new activities to previously characterized compounds, compound libraries are also an ideal source of adjuvants, molecules that have little to no antibiotic activity alone but can be used in combination with other drugs to enhance antimicrobial activity and, in some cases, circumvent resistance mechanisms (26)(27)(28). For example, we found that the vitamin D derivative doxercalciferol acts synergistically with bacitracin through a mechanism involving the S. mutans bacitracin resistance transporter, MBR (29).…”

Investigation on the effect of vitamin C on growth & biofilm-forming potential of Streptococcus mutans isolated from patients with dental caries

“…The MIC for both vitamin C and gentamicin was measured using the same strains under the same conditions. FICI was interpreted according to standard de nitions, wherein a FICI of ≤ 0.5 was determined as a synergistic effect, a FICI of > 4.0 was determined as an antagonistic effect, and a FICI between 0.51 and 3.99 was determined as no interaction [39,40]. Line graph showing the relationship between absorbance at 560 nm and increasing vitamin C concentrations in the bio lm and growth assays.…”