Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

Boersch, Mark; Rudrawar, Santosh; Grant, Gary; Zunk, Matthew

doi:10.1039/c7ra12950e

Cited by 41 publications

(39 citation statements)

References 42 publications

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“…This also demonstrates a possible energy saving potential in cell maintenance through more efficient biosynthesis, www.nature.com/scientificreports www.nature.com/scientificreports/ which might also lead to better cell yields at low temperature 39 . Overall we could not observe significant changes in expression of genes involved in menaquinone synthesis 40 . This was in accord with the minor changes in menaquinone content at different growth temperatures (Table 1).…”

Section: Discussioncontrasting

confidence: 57%

Carotenoids are used as regulators for membrane fluidity by Staphylococcus xylosus

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et al. 2020

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carotenoids are associated with several important biological functions as antenna pigments in photosynthesis or protectives against oxidative stress. Occasionally they were also discussed as part of the cold adaptation mechanism of bacteria. For two Staphylococcus xylosus strains we demonstrated an increased content of staphyloxanthin and other carotenoids after growth at 10 °C but no detectable carotenoids after grow at 30 °C. By in vivo measurements of generalized polarization and anisotropy with two different probes Laurdan and TMA-DPH we detected a strong increase in membrane order with a simultaneous increase in membrane fluidity at low temperatures accompanied by a broadening of the phase transition. Increased carotenoid concentration was also correlated with an increased resistance of the cells against freeze-thaw stress. In addition, the fatty acid profile showed a moderate adaptation to low temperature by increasing the portion of anteiso-branched fatty acids. The suppression of carotenoid synthesis abolished the effects observed and thus confirmed the causative function of the carotenoids in the modulation of membrane parameters. A differential transcriptome analysis demonstrated the upregulation of genes involved in carotenoid syntheses under low temperature growth conditions. The presented data suggests that upregulated synthesis of carotenoids is a constitutive component in the cold adaptation strategy of Staphylococcus xylosus and combined with modifications of the fatty acid profile constitute the adaptation to grow under low temperature conditions. Carotenoids represent a large group and comprise at least 800 described compounds 1,2 which are synthesized from isoprene units by phototrophic and chemoorganotrophic prokaryotes, plants, fungi, and algae 3. Most carotenoids consist of eight isoprene units resulting in a C40 backbone and usually display β-cyclisation 1,4. Only a few chemoorganotrophic bacteria are capable of producing C30, C45 or C50 carotenoids 4,5. Such a rare C30 carotenoid is produced by staphylococci 6,7. As lipophilic compounds, carotenoids are located in the cell membrane, but their orientation inside the membrane may vary depending on their chemical structure and on the thickness of the membrane 8,9. They perform important biological functions such as light harvesting as antenna pigments 10,11 , provide protection against oxidative stress 5,12 , provide protection from ultraviolet radiation 13,14 , and stabilization of pigment proteins 15. In addition to the functions mentioned above, the involvement of carotenoids in cold adaptation was suspected 16-18. We assumed that carotenoids might have a similar function in regulating membrane fluidity as sterols such as cholesterol or ergosterol in eukaryotic cells. They increase membrane order with concurrent maintenance of lateral lipid motility, which results in a liquid-ordered membrane state 19. Similar mechanisms were previously described for the bacterial sterol-like hopanoids 20,21 and isoprenoid quinones 22. In vitro studies wit...

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Section: Discussioncontrasting

confidence: 57%

Carotenoids are used as regulators for membrane fluidity by Staphylococcus xylosus

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Baust

Sons

et al. 2020

Sci Rep

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“…These enzymes catalyze the oxidation of NADH to NAD + and succinate to fumarate, respectively, followed by the menaquinone/menaquinol reduction. The menaquinone/menaquinol redox pool then transfers the electrons to a final acceptor (oxygen in aerobic conditions and nitrate or fumarate in anaerobic conditions) via terminal respiratory oxidases, while protons are pumped across the membrane, generating the PMF [ 17 , 18 , 19 ]. Despite an emerging role of fumarate reductase and nitrate reductase under hypoxia, in such conditions, the redox mediated by these enzymes is poorly understood, and a major focus is still given to the cytochrome bc1-aa3 “supercomplex” and the cytochrome bd oxidase, acknowledged to play a vital role in aerobic conditions.…”

Section: Energy-metabolism In Mycobacterium Tuberculosismentioning

confidence: 99%

“…It is well known that menaquinone (vitamin K2) plays an important role in producing the electrochemical gradient required for the production of ATP in ETC by shuttling electrons to terminal reductases. Therefore, each step involved in menaquinone biosynthesis, catalyzed by Men enzymes (MenA-J), is a potential chemotherapeutic target; besides, unlike bacteria, human cells are unable to produce menaquinone ex novo , as it is obtained only through the diet [ 17 , 18 , 19 ]. The most promising results come from inhibitors of Men-enzymes that function downstream of the synthesis pathway (MenA, MenB, MenG), of which DG70 is the most recent compound.…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

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“…Since MK is a central component in the respiratory chain of mycobacteria, and humans do not utilize MK in their ETC, MK synthesis is receiving considerable interest as an attractive target for development of novel chemotherapeutics [3–9] to combat M . tuberculosis and potentially other pathogens that exclusively synthesize this compound.…”

Section: Introductionmentioning

confidence: 99%

Characterization of MenA (isoprenyl diphosphate:1,4-dihydroxy-2-naphthoate isoprenyltransferase) from Mycobacterium tuberculosis

et al. 2019

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The menaquinone biosynthetic pathway presents a promising drug target against Mycobacterium tuberculosis and potentially other Gram-positive pathogens. In the present study, the essentiality, steady state kinetics of MenA from M . tuberculosis and the mechanism of MenA inhibition by Ro 48–8071 were characterized. MenA [isoprenyl diphosphate:1,4-dihydroxy-2-naphthoate (DHNA) isoprenyltransferase] catalyzes a critical reaction in menaquinone biosynthesis that involves the conversion of cytosolic DHNA, to membrane bound demethylmenaquinone by transferring a hydrophobic 45-carbon isoprenoid chain (in the case of mycobacteria) to the ring nucleus of DHNA. Rv0534c previously identified as the gene encoding MenA in M . tuberculosis complemented a menA deletion in E . coli and an E . coli host expressing Rv0534c exhibited an eight-fold increase in MenA specific activity over the control strain harboring empty vector under similar assay conditions. Expression of Rv0534c is essential for mycobacterial survival and the native enzyme from M . tuberculosis H37Rv was characterized using membrane preparations as it was not possible to solubilize and purify the recombinant enzyme. The enzyme is absolutely dependent on the presence of a divalent cation for optimal activity with Mg +2 being the most effective and is active over a wide pH range, with pH 8.5 being optimal. The apparent K m values for DHNA and farnesyl diphosphate were found to be 8.2 and 4.3 μM, respectively. Ro 48–8071, a compound previously reported to inhibit mycobacterial MenA activity, is non-competitive with regard to DHNA and competitive with regard to the isoprenyldiphosphate substrate.

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Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

Abstract: Menaquinone is essential in electron transport and ATP generation in all Gram-positive, and anaerobically respiring Gram-negative bacteria. Inhibition of menaquinone production at different steps of the biosynthesis pathway has shown promising novel antibacterial action.

Cited by 41 publications

References 42 publications

Carotenoids are used as regulators for membrane fluidity by Staphylococcus xylosus

Carotenoids are used as regulators for membrane fluidity by Staphylococcus xylosus

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

Characterization of MenA (isoprenyl diphosphate:1,4-dihydroxy-2-naphthoate isoprenyltransferase) from Mycobacterium tuberculosis

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