Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis

Imai, Yu; Hauk, Glenn; Quigley, Jeffrey; Liang, Libang; Son, Sangkeun; Ghiglieri, Meghan; Gates, Michael F.; Morrissette, Madeleine; Shahsavari, Negar; Niles, Samantha; Baldisseri, Donna M.; Honrao, Chandrashekhar; Ma, Xiaoyu; Guo, Jason; Lewis, Kim

doi:10.1038/s41589-022-01102-7

Cited by 27 publications

(17 citation statements)

References 55 publications

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“…However, the success of whole-cell screening, including early counterscreening of human cells for safety, seems to have been effective in discovering two new classes of Gram-negative targeting antibiotics [ 5 , 13 ]. A similar approach, although starting with a natural product, recently lead to the discovery of evybactin, a new M. tuberculosis DNA gyrase-targeting compound [ 62 ]; this compound appears to work in a similar manner to the thiophene inhibitors [ 63 ] that allosterically stabilize DNA cleavage complexes [ 64 ] by binding to a ‘third site’—a hinge pocket [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase

Morgan

Lipka-Lloyd

Warren

et al. 2023

IJMS

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Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water–metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.

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Section: Discussionmentioning

confidence: 99%

A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase

Morgan

Lipka-Lloyd

Warren

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…However, the success of whole cell screening, including early counter-screening of human cells for safety seems to have been effective in discovering two new classes of Gram-negative targeting antibiotics [5, 13]. A similar approach, but starting with a natural product, has recently lead to the discovery of evybactin a new class on M. tuberculosis DNA gyrase targeting compound [57]; this compound appears to work in a similar manner to the thiophene inhibitors [58] compounds that allosterically stabilize DNA-cleavage complexes [59] by binding to a ‘third-site’; a hinge pocket [10].…”

Section: Discussionmentioning

confidence: 99%

A 2.8 Å structure of zoliflodacin in a DNA-cleavage complex withStaphylococcus aureusDNA gyrase

Morgan

Lipka-Lloyd

Warren

et al. 2022

Preprint

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Since 2000 some thirteen quinolones/fluoroquinolones have been developed and come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA-cleavage complexes with DNA gyrase and topo IV, the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here we report a 2.8 Å X-ray crystal structure which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA-cleavage site(s) as quinolones sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water-metal ion bridge to GyrA) suggesting it may be more difficult for bacteria to develop target mediated resistance. We found that zoliflodacin had an MIC of 4µg/mL againstAcinetobacter baumannii, an improvement of 4-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, are likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.

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“…MdtM is an efflux pump that extrudes antibiotics from the bacterial cytosol [28]. SbmA is a homodimer proton-driven transporter found among some classes of Proteobacteria [2], which is involved in uptake of non-ribosomal peptide antibiotics [29], ribosomally synthesized and post-translationally modified peptides [30], and PrAMPs [1]. BacA in Sinorhizobium meliloti is important for establishing effective symbiosis with leguminous plants [31].…”

Section: Resistance To Bac7 1-22 In the Salt-containing Medium Is Med...mentioning

confidence: 99%

Genomic Insights into Bacterial Resistance to Proline-Rich Antimicrobial Peptide Bac7

et al. 2023

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Proline-rich antimicrobial peptides (PrAMPs) having a potent antimicrobial activity and a modest toxicity toward mammalian cells attract much attention as new templates for the development of antibiotic drugs. However, a comprehensive understanding of mechanisms of bacterial resistance development to PrAMPs is necessary before their clinical application. In this study, development of the resistance to the proline-rich bovine cathelicidin Bac71-22 derivative was characterized in the multidrug-resistant Escherichia coli clinical isolate causing the urinary tract infection. Three Bac71-22-resistant strains with ≥16-fold increase in minimal inhibitory concentrations (MICs) were selected by serially passaging after four-week experimental evolution. It was shown that in salt-containing medium, the resistance was mediated by inactivation of the SbmA transporter. The absence of salt in the selection media affected both dynamics and main molecular targets under selective pressure: a point mutation leading to the amino acid substitution N159H in the WaaP kinase responsible for heptose I phosphorylation in the LPS structure was also found. This mutation led to a phenotype with a decreased susceptibility to both the Bac71-22 and polymyxin B. Screening of antimicrobial activities with the use of a wide panel of known AMPs, including the human cathelicidin LL-37 and conventional antibiotics, against selected strains indicated no significant cross-resistance effects.

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Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis

Cited by 27 publications

References 55 publications

A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase

A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase

A 2.8 Å structure of zoliflodacin in a DNA-cleavage complex withStaphylococcus aureusDNA gyrase

Genomic Insights into Bacterial Resistance to Proline-Rich Antimicrobial Peptide Bac7

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