Structural Basis of Resistance to Anti-Cytochrome bc₁ Complex Inhibitors: Implication for Drug Improvement

Abstract

The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives.

Can All Major ROS Forming Sites of the Respiratory Chain Be Activated By High FADH2/NADH Ratios?

“…Reconstructed structures allowed the location of major catalytic components in the complex . This structural information helped to get the Q‐cycle mechanism broadly accepted, though differences with regard to the precise sequence of events involving the partial redox reactions that occur remain. An “activated” Q‐cycle mechanism in which QH 2 oxidation at the Qn site primes the complex for catalysis at the Qp site first is championed by Mulkidjanian .…”

Strobilurin fungicides in house dust: is wallboard a source?

“…Strobilurin pesticides, which include azoxystrobin, pyraclostrobin, fluoxastrobin, and trifloxystrobin, are fungicides originally derived from the fungus Strobilurus tenacellus and are most commonly applied to fruits and vegetables. Strobilurin fungicides act as disruptors of mitochondrial respiration by binding to Q O sites of the cytochrome bc 1 complex in target fungi [1]. Given that mitochondria are the target of these fungicides, they may potentially elicit a wide range of acute and chronic toxic effects.…”

Differentiation of Pythium spp. from vegetable crops with molecular markers and sensitivity to azoxystrobin and mefenoxam

“…Decreased sensitivity to azoxystrobin may also be based on a compensation of the energy deficit induced by the fungicide upstream of the NADH dehydrogenase in the respiratory chain as proposed for V. inaequalis . through modification of the alternative oxidase gene, or through reduced accumulation of bc1 inhibitor . On the other hand, the reduced sensitivity is obviously not related to the presence of intron directly before or after codon 143, as found in rusts, and Monilia spp., since no intron was detected in the cyt b gene in the studied Pythium spp.…”