The myxopyronins, new inhibitors of bacterial RNA synthesis from Myxococcus fulvus (Myxobacterales).

Abstract

From the culture supernatant of the myxobacterium, Myxococcus fulvus strain Mx f50, an antibiotic activity was isolated which blocked growth of many Gram-positive and several Gramnegative bacteria, but not of yeasts and fungi. The activity consisted of two closely related compounds, myxopyronins A and B. The myxopyronins appear to be new antibiotics, and seem to specifically inhibit bacterial RNA polymerase.In this article, we present data on a new antibacterial compound, myxopyronin ( Fig. 1)1), which was discovered in a screening program for antibiotics from myxobacteria.After myxothiazol">, myxovirescin3>, myxovalargin4), and myxalamid1>, this is now the fifth new antibiotic which we could isolate from these unusual and little studied organisms. In addition, we found two antibiotics, pyrrolnitrine> and althiomycin7>, that were already known from other bacteria. We describe here the fermentation and •2H0O; pH adjusted to 7.2 before autoclaving. In this medium, the organism grew as a homogeneous cell suspension.

Bacterial Transcription as a Target for Antibacterial Drug Development

“…2) were isolated from cultures of Myxococcus fulvus and displayed broad-spectrum antibacterial activity against Gram-positive and -negative bacteria by inhibiting transcription initiation (133,134). Mechanistic studies showed that myxopyronins bind to the switch region and lock the clamp and switch regions in a partly closed/fully closed conformation.…”

“…Although the switch region is conserved across prokaryotic and eukaryotic RNAPs, the adjacent segments are conserved only in bacterial RNAPs, which may explain the specificity of myxopyronins against bacteria (132,133). It was shown that ␤ E1272, E1279, and S1322 and ␤= G344, K345, and K1348 were involved in polar interactions with both myxopyronin A and 8-desmethyl myxopyronin B. Mutagenesis studies demonstrated that amino acid substitutions at ␤ residues E1279 and S1322 and ␤= residue K345 generated resistance against 8-desmethyl myxopyronin B, while changes at ␤ V1275 and L1291 and ␤= K345 resulted in resistance to myxopyronin A (132,135).…”

Total synthesis of antibiotics: recent achievements, limitations, and perspectives

“…fulvus HR4, DSM 2549), respectively. (Irschik,1985;198378) Their common structural motive is a 4-hydroxy--pyrone ring with two side chains attached at C3 and C6 positions. A crystal structure of RNA-polymerase-myxopyronin complex was obtained by Ebright and co-workers identified the "switch region"…”

Frequency, Spectrum, and Nonzero Fitness Costs of Resistance to Myxopyronin in Staphylococcus aureus

“…The resistance rate for Myx is 4 ؋ 10 ؊8 to 7 ؋ 10 ؊8 per generation, which is equal within error to the resistance rate for Rif (3 ؋ 10 ؊8 to 10 ؋ 10 ؊8 per generation). Substitutions conferring Myx resistance were obtained in the RNAP ␤ subunit [six substitutions: V1080(1275)I, V1080(1275)L, E1084(1279)K, D1101(1296)E, S1127(1322)L, and S1127 (1322) Mf50 (18,20,23,49). Myx exhibits broad-spectrum antibacterial activity, with potent antibacterial activity against most Gram-positive species and some Gram-negative species.…”