Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes

Stringer, Tameryn; Seldon, Ronnett; Liu, Nicole; Warner, Digby F.; Tam, Christina; Cheng, Luisa W.; Land, Kirkwood M.; Smith, Peter J.; Chibale, Kelly; Smith, Gregory S.

doi:10.1039/c7dt01952a

Cited by 49 publications

(19 citation statements)

References 72 publications

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“…Compounds were screened against Mycobacterium tuberculosis (Mtb) H37Rv::gfp, an engineered reporter strain that constitutively expresses green fluorescent protein (GFP), in a broth microdilution assay with rifampicin as a reference. As detailed previously 52 (Table 1).…”

Section: Resultsmentioning

confidence: 96%

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

et al. 2018

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The quinolone decoquinate is coadministered with feed for treatment of parasites which cause coccidiosis in poultry. However, from a drug-development perspective, the biological activity is often not adequately exploited due to poor physicochemical properties. Here we convert decoquinate into N-alkyl quinolone amides that, in contrast to decoquinate, are active against the tuberculosis bacterium with MIC 90 values ranging from 1.4 to 3.64 µM, and quinoline O-carbamates active against apicomplexan parasites that cause malaria, toxoplasmosis, and neosporosis with IC 50 values of 0.32-1.5 nM for the best derivative. Uniquely for the TB-active amides, disruption of cell wall homoeostasis is identified as one target. With IC 50 values against fetal lung fibroblast cells of 40 to >100 μM, the derivatives are selective for the pathogens. Structures of the most active derivatives are determined by NMR spectroscopy and X-ray crystallography. Analogues lacking the decyl side chain of decoquinate are inactive.

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Section: Resultsmentioning

confidence: 96%

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

et al. 2018

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“…Nonphysiological conditions may obscure potent inhibitory activity of compounds during antimicrobial screening, particularly inhibitors of metabolic processes that are functional and essential only in the in vivo context (cryptic drug targets). This is illustrated by the carbon source dependence of inhibitors of the glyoxylate shunt in gram-negative pathogens [ 6 – 8 ]. Identifying growth condition-dependent hits that lack in vivo activity is also problematic.…”

Section: Introductionmentioning

confidence: 99%

Growth medium-dependent antimicrobial activity of early stage MEP pathway inhibitors

et al. 2018

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The in vivo microenvironment of bacterial pathogens is often characterized by nutrient limitation. Consequently, conventional rich in vitro culture conditions used widely to evaluate antibacterial agents are often poorly predictive of in vivo activity, especially for agents targeting metabolic pathways. In one such pathway, the methylerythritol phosphate (MEP) pathway, which is essential for production of isoprenoids in bacterial pathogens, relatively little is known about the influence of growth environment on antibacterial properties of inhibitors targeting enzymes in this pathway. The early steps of the MEP pathway are catalyzed by 1-deoxy-d-xylulose 5-phosphate (DXP) synthase and reductoisomerase (IspC). The in vitro antibacterial efficacy of the DXP synthase inhibitor butylacetylphosphonate (BAP) was recently reported to be strongly dependent upon growth medium, with high potency observed under nutrient limitation and exceedingly weak activity in nutrient-rich conditions. In contrast, the well-known IspC inhibitor fosmidomycin has potent antibacterial activity in nutrient-rich conditions, but to date, its efficacy had not been explored under more relevant nutrient-limited conditions. The goal of this work was to thoroughly characterize the effects of BAP and fosmidomycin on bacterial cells under varied growth conditions. In this work, we show that activities of both inhibitors, alone and in combination, are strongly dependent upon growth medium, with differences in cellular uptake contributing to variance in potency of both agents. Fosmidomycin is dissimilar to BAP in that it displays relatively weaker activity in nutrient-limited compared to nutrient-rich conditions. Interestingly, while it has been generally accepted that fosmidomycin activity depends upon expression of the GlpT transporter, our results indicate for the first time that fosmidomycin can enter cells by an alternative mechanism under nutrient limitation. Finally, we show that the potency and relationship of the BAP-fosmidomycin combination also depends upon the growth medium, revealing a striking loss of BAP-fosmidomycin synergy under nutrient limitation. This change in BAP-fosmidomycin relationship suggests a shift in the metabolic and/or regulatory networks surrounding DXP accompanying the change in growth medium, the understanding of which could significantly impact targeting strategies against this pathway. More generally, our findings emphasize the importance of considering physiologically relevant growth conditions for predicting the antibacterial potential MEP pathway inhibitors and for studies of their intracellular targets.

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“…1 Reports reveal that the analogues of pyrazine and pyrazinamide can exhibit higher anti-TB activity against MTB. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] Substituted N-phenylpyrazine-2-carboxamides synthesized by Dolezal et al were evaluated in vitro for antimycobacterial activity. It was shown that compound N-(4-(triuoromethyl)phenyl)pyrazine-2-carboxamide (A), N-(2bromo-3-methylphenyl)pyrazine-2-carboxamide (B) and N-(3iodo-4-methylphenyl)pyrazine-2-carboxamide (C) exhibited four times higher activity (MIC # 2 mg L À1 ) than the standard drug PZA (¼8 mg L À1 ).…”

Section: Introductionmentioning

confidence: 99%

Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents

et al. 2020

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Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes

Cited by 49 publications

References 72 publications

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

Growth medium-dependent antimicrobial activity of early stage MEP pathway inhibitors

Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents

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