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2.B.8 The Bafilomycin A1 (Bafilomycin) Family

Bafilomycin A1 is a macrolide antibiotic from Streptomyces spp. known as an inhibitor of V-ATPases (Gagliardi et al., 1999). Bafilomycin A1 induces uptake of potassium ions by energized mitochondria and causes mitochondrial swelling, loss of membrane potential, uncoupling of oxidative phosphorylation, and inhibition of the maximal respiration rates. It also induced pyridine nucleotide oxidation. The mitochondrial effects provoked by nanomolar concentrations of bafilomycin A1 were connected to its activity as a potent, K+-specific ionophore. The K+ ionophoric activity of bafilomycin A1 was observed also in black lipid membranes. Bafilomycin A1 is a K+ carrier but not a channel former. Bafilomycin A1 is the first and currently unique macrolide antibiotic with K+ ionophoric properties. The novel properties of bafilomycin A1 may explain some of the biological effects of this plecomacrolide antibiotic, independent of V-ATPase inhibition (Teplova et al., 2007).

Bafilomycin A1 (BafA1), which is a member of the plecomacrolide sub-class of macrolide antibiotics, has differential, concentration-dependent effects on neuronal cell viability (Shacka et al., 2006). When used at high concentrations, BafA1 inhibits vacuolar ATPase (V-ATPase), promotes the accumulation of autophagic vacuoles and triggers Bax-dependent apoptosis. These effects are similar to those induced by the lysosomotropic agent chloroquine. Conversely, at concentrations below its reported ability to completely inhibit V-ATPase, BafA1 dramatically attenuates chloroquine-induced apoptosis. The protective effects of BafA1 appear to be independent of the chloroquine-induced accumulation of autophagosomes. Rather, BafA1 appears to inhibit events downstream of chloroquine-induced autophagosome accumulation, such as the loss of mitochondrial or lysosomal integrity. BafA1 inhibits the death of neurons induced by autophagic stress/inhibition. Neuroprotection against chloroquine-induced death is also provided by plecomacrolide antibiotics that are structurally similar to BafA1, including bafilomycin B1 and concanamycin A (Shacka et al., 2006).

The generalized reaction catalyzed by bafilomycin is:

K+ (in) K+ (out)

References associated with 2.B.8 family:

Gagliardi, S., M. Rees, and C. Farina. (1999). Chemistry and structure activity relationships of bafilomycin A1, a potent and selective inhibitor of the vacuolar H+-ATPase. Curr. Med. Chem. 6(12):1197-1212. 10519916
Shacka, J.J., B.J. Klocke, and K.A. Roth. (2006). Autophagy, bafilomycin and cell death: the 'a-B-cs' of plecomacrolide-induced neuroprotection. Autophagy. 2(3):228-230.
Teplova, V.V., A.A. Tonshin, P.A. Grigoriev, N.E. Saris, and M.S. Salkinoja-Salonen. (2007). Bafilomycin A1 is a potassium ionophore that impairs mitochondrial functions. J. Bioenerg. Biomembr. 39(4):321-329. 17917797