Progesterone Analogs Influence Germination of Clostridium sordellii and Clostridium difficile Spores In Vitro

Abstract

Clostridium sordellii and Clostridium difficile are closely related anaerobic Gram-positive, spore-forming human pathogens. C. sordellii and C. difficile form spores that are believed to be the infectious form of these bacteria. These spores return to toxin-producing vegetative cells upon binding to small molecule germinants. The endogenous compounds that regulate clostridial spore germination are not fully understood. While C. sordellii spores require three structurally distinct amino acids to germinate, the occurrence of postpregnancy C. sordellii infections suggests that steroidal sex hormones might regulate its capacity to germinate. On the other hand, C. difficile spores require taurocholate (a bile salt) and glycine (an amino acid) to germinate. Bile salts and steroid hormones are biosynthesized from cholesterol, suggesting that the common sterane structure can affect the germination of both C. sordellii and C. difficile spores. Therefore, we tested the effect of sterane compounds on C. sordellii and C. difficile spore germination. Our results show that both steroid hormones and bile salts are able to increase C. sordellii spore germination rates. In contrast, a subset of steroid hormones acted as competitive inhibitors of C. difficile spore germination. Thus, even though C. sordellii and C. difficile are phylogenetically related, the two species' spores respond differently to steroidal compounds.

The desA and desB genes from Clostridium scindens ATCC 35704 encode steroid-17,20-desmolase

“…Androgens directly affect bacterial growth and virulence [37][38][39]. Intriguingly, steroids have been shown to influence C. difficile germination [40]. 11β-hydroxy-androgens are also inhibitors of the host enzyme 11β-HSD2 [41,42], but in kidney and vascular smooth muscle may be pro-hypertensive [42].…”

Germinants and Their Receptors in Clostridia

“…Although C. sordellii germinates in response to growth-promoting germinants (Table 1), C. sordellii spore germination also is enhanced by progesterone and progesterone-based steroids (cholesterol derivatives), as well as certain bile acids (45,62). This pathogen causes serious infection in postpartum women or in medically induced abortions using mifepristone (63).…”

“…This pathogen causes serious infection in postpartum women or in medically induced abortions using mifepristone (63). The hormonal changes that occur in postpartum women, or mifepristone itself, are hypothesized to prime or enhance germination by C. sordellii spores and thus initiate colonization of the host (45).…”

“…L-arginine (43,58) Cholic acid and related bile acids (43,59,60) CDCA and related bile acids, progesterone, and related derivatives (43,45,67,68) C. frigidicarnis doglycan, glycine also is important for optimal growth of the organism (50,51). C. difficile can oxidatively deaminate and decarboxylate amino acids in Stickland metabolism to generate ATP and NADH (52).…”

“…Germinants, most commonly, are amino acids, but other molecules (e.g., cholesterol-based compounds, organic acids, nucleosides, peptidoglycan fragments, etc.) have been identified (41)(42)(43)(44)(45)(46). Although germination of some spores can be triggered by a simple germinant, some spores require the presence of more than one type of molecule to stimulate germination (35).…”