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are dispensable.9 We proposed that trans-Δ1-NQNO mimics the
native menaquinone (MK) / menaquinol (MKH2) redox couple
that shuttles electrons in the respiratory chain.9, 22 This model is
further supported by multiple studies that have used saturated
AQNOs in co-crystallisation with various enzymes featuring a
ubiquinone or menaquinone binding site.23-26
We here demonstrate that 3-methylation of the quinolone core
considerably contributes to complete and long-lasting inhibition
of growth and metabolic activity. This is in line with the
proposed mechanism of action, since methylation further
increases the structural resemblance of quinolone N-oxides to
menaquinones (Fig. 4). Quinolone methylation is a unique but
modular step that Burkholderia may have developed to further
improve antibiotic activity of quinolone N-oxides against
competitors like S. aureus. Interestingly, unsaturation of AQNOs
and MAQNOs in Δ1-position increased antibiotic activity in
comparison to Δ2-position, which is also the position of
unsaturation in menaquinones. It is possible that the Δ1-
position reduces structural flexibility of the inhibitors in the
binding site of the target proteins and thereby improves
activity.
DOI: 10.1039/D0CC02498H
KoRS-CB (DS) and the Zeiss foundation (MP).
Notes and references
§MAQs and MAQNOs have also been termed HMAQs and
HMAQNOs relating to their tautomeric 4-hydroxy-3-methyl-2-
alkyl-4(1H)-quinolone form and their respective N-oxides. We
prefer the abbreviation MAQs and MAQNOs to be consistent with
the nomenclature of AQs and AQNOs.
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Figure 4 Structural analogy of the menaquinone (MK) /
menaquinol (MKH2) redox couple and the tautomers of
quinolone N-oxides.
In conclusion, we show that methylation and unsaturation in Δ1-
position greatly enhanced antibiotic potency while the
unsaturation in Δ2-position displayed activity only in
combination with methylation. Strikingly, B. thailandensis and
P. aeruginosa produced those quinolone N-oxides that scored
among the most active ones in concentrations close to or even
above their MIC value against S. aureus. This suggests that in
particular unsaturated AQNOs and MAQNOs may have an
important role for Pseudomonas and Burkholderia strains in
competitive interactions with S. aureus. However, that fact that
also metabolites of less potent classes are produced indicates
functional differentiation with potential further roles in
interspecies competition with other microbes or in pathogen
host interactions.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We thank Prof. Dr. Andreas Marx and his group for their
generous support and Prof. Dr. Tanja Gaich for using their mass
spectrometer. This work was funded by the Emmy Noether
4 | Chem. Commun., 2020, 00, 1-3
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