Synthesis, docking and antibacterial studies of more potent amine and hydrazone rifamycin congeners than rifampicin

Pyta, Krystian; Janas, Anna; Szukowska, Monika; Pecyna, Paulina; Jaworska, Marcelina M.; Gajęcka, Marzena; Bartl, Franz; Przybylski, Piotr

doi:10.1016/j.ejmech.2019.02.009

Cited by 28 publications

(21 citation statements)

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“…Pyrazole derivatives are another class of pharmacologically important molecules known for their wide range of therapeutic properties including antimicrobial activities [18,19,20]. Likewise, hydrazone derivatives are known for their wide range of biological activities including antibacterial properties; e.g., rifampicin, an approved drug to treat tuberculosis [21,22].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

et al. 2019

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Microbial resistance to drugs is an unresolved global concern, which is present in every country. Developing new antibiotics is one of the guidelines of the Centers for Disease Control and Preventions (CDC) to combat bacterial resistance to drugs. Based on our lead molecules, we report the synthesis and antimicrobial studies of 27 new pyrazole derivatives. These new coumarin-pyrazole-hydrazone hybrids are readily synthesized from commercially available starting materials and reagents using benign reaction conditions. All the synthesized molecules were tested against 14 Gram-positive and Gram-negative bacterial strains. Several of these molecules have been found to be potent growth inhibitors of several strains of these tested bacteria with minimum inhibitory concentrations as low as 1.56 μg/mL. Furthermore, active molecules are non-toxic in in vitro and in vivo toxicity studies.

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Section: Introductionmentioning

confidence: 99%

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

et al. 2019

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“…Several previous studies have confirmed the formation of zwitterionic structures and their derivatives in rifamycin [14]. The improvement of water solubility and lipophilicity enhanced rifamycins' biological potency [15]. In addition, it was reported that proton transfer processes within rifampicin analogs influenced their biological activity [14,16].…”

Section: Introductionmentioning

confidence: 83%

“…'Click chemistry' was reported to have been successfully applied to the modification of rifamycins [14]. After many active rifamycin antibiotics had been modified, they exhibited better anti-tuberculosis activity [15]. Moreover, the form of rifamycin in solution is closely related to its biological activity.…”

Section: Introductionmentioning

confidence: 99%

Enniatin A1, A Natural Compound with Bactericidal Activity against Mycobacterium tuberculosis In Vitro

Wang

Lü

et al. 2019

Molecules

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Background: Tuberculosis remains a global disease that poses a serious threat to human health, but there is lack of new and available anti-tuberculosis agents to prevent the emergence of drug-resistant strains. To address this problem natural products are still potential sources for the development of novel drugs. Methods: A whole-cell screening approach was utilized to obtain a natural compound enniatin A1 from a natural products library. The target compound's antibacterial activity against Mycobacterium tuberculosis (M. tuberculosis) was evaluated by using the resazurin reduction micro-plate assay (REMA) method. The cytotoxicity of the compound against Vero cells was measured to calculate the selectivity index. The intracellular inhibition activity of enniatin A1 was determined. We performed its time-kill kinetic assay against M. tuberculosis. We first tested its synergistic effect in combination with the first and second-line anti-tuberculosis drugs. Finally, we measured the membrane potential and intracellular ATP levels of M. tuberculosis after exposure to enniatin A1. Results: We identified enniatinA1 as a potential antibacterial agent against M. tuberculosis, against which it showed strong selectivity. Enniatin A1 exhibited a time-concentration-dependent bactericidal effect against M. tuberculosis, and it displayed synergy with rifamycin, amikacin, and ethambutol. After exposure to enniatinA1, the membrane potential and intracellular ATP levels of M. tuberculosis was significantly decreased. Conclusions: Enniatin A1 exhibits the positive potential anti-tuberculosis agent characteristics.

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“…Together, these data are consistent with a mechanism where Rox enzymes hydroxylate C2 of the naphthoquinone core, leading to cleavage of the C−N bond at C2 and opening of the ansa chain (Figure 5B). To unequivocally demonstrate that C2 is hydroxylated, we made use of a well-known isotope effect whereby 18 O will produce a shift in 13 C NMR, relative to a carbon bound to 16 O. 50 We performed in vitro oxidation of rifaximin under an 18 O 2 enriched atmosphere achieving 44% incorporation of the 18 O label.…”

Section: ■ Rif Monooxygenase (Rox)mentioning

confidence: 99%

The Enzymes of the Rifamycin Antibiotic Resistome

2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Rifamycin antibiotics include the WHO essential medicines rifampin, rifabutin, and rifapentine. These are semisynthetic derivatives of the natural product rifamycins, originally isolated from the soil bacterium Amycolatopsis rifamycinica. These antibiotics are primarily used to treat mycobacterial infections, including tuberculosis. Rifamycins act by binding to the β-subunit of bacterial RNA polymerase, inhibiting transcription, which results in cell death. These antibiotics consist of a naphthalene core spanned by a polyketide ansa bridge. This structure presents a unique 3D configuration that engages RNA polymerase through a series of hydrogen bonds between hydroxyl groups linked to the naphthalene core and C21 and C23 of the ansa bridge. This binding occurs not in the enzyme active site where template-directed RNA synthesis occurs but instead in the RNA exit tunnel, thereby blocking productive formation of full-length RNA. In their clinical use to treat tuberculosis, resistance to rifamycin antibiotics arises principally from point mutations in RNA polymerase that decrease the antibiotic's affinity for the binding site in the RNA exit tunnel. In contrast, the rifamycin resistome of environmental mycobacteria and actinomycetes is much richer and diverse. In these organisms, rifamycin resistance includes many different enzymatic mechanisms that modify and alter the antibiotic directly, thereby inactivating it. These enzymes include ADP ribosyltransferases, glycosyltransferases, phosphotransferases, and monooxygenases. ADP ribosyltransferases catalyze group transfer of ADP ribose from the cofactor NAD + , which is more commonly deployed for metabolic redox reactions. ADP ribose is transferred to the hydroxyl linked to C23 of the antibiotic, thereby sterically blocking productive interaction with RNA polymerase. Like ADP ribosyltransferases, rifamycin glycosyl transferases also modify the hydroxyl of position C23 of rifamycins, transferring a glucose moiety from the donor molecule UDP-glucose. Unlike other antibiotic resistance kinases that transfer the γ-phosphate of ATP to inactivate antibiotics such as aminoglycosides or macrolides, rifamycin phosphotransferases are ATP-dependent dikinases. These enzymes transfer the β-phosphate of ATP to the C21 hydroxyl of the rifamycin ansa bridge. The result is modification of a critical RNA polymerase binding group that blocks productive complex formation. On the other hand, rifamycin monooxygenases are FAD-dependent enzymes that hydroxylate the naphthoquinone core. The result of this modification is untethering of the ansa chain from the naphthyl moiety, disrupting the essential 3D shape necessary for productive RNA polymerase binding and inhibition that leads to cell death.All of these enzymes have homologues in bacterial metabolism that either are their direct precursors or share common ancestors to the resistance enzyme. The diversity of these resistance mechanisms, often redundant in individual bacterial isolates, spea...

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Synthesis, docking and antibacterial studies of more potent amine and hydrazone rifamycin congeners than rifampicin

Cited by 28 publications

References 43 publications

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

Synthesis of Hydrazone Derivatives of 4-[4-Formyl-3-(2-oxochromen-3-yl)pyrazol-1-yl]benzoic acid as Potent Growth Inhibitors of Antibiotic-resistant Staphylococcus aureus and Acinetobacter baumannii

Enniatin A1, A Natural Compound with Bactericidal Activity against Mycobacterium tuberculosis In Vitro

The Enzymes of the Rifamycin Antibiotic Resistome

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