4-Aminothiazolyl Analogues of GE2270 A: Antibacterial Lead Finding

LaMarche, Matthew J.; Leeds, Jennifer A.; Dzink-Fox, JoAnne; Gunderson, Karl; Krastel, Philipp; Memmert, Klaus; Patane, Michael A.; Rann, Elin M.; Schmitt, E.; Tiamfook, Stacey; Wang, Bing

doi:10.1021/jm101602q

Cited by 35 publications

(18 citation statements)

References 24 publications

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“…Both compounds exhibited potent activities against the Gram-positive strains tested and were ineffective against the Gram-negative strains (Table 1). This spectrum is consistent with that observed for natural product GE2270 A (Table 1) (10, 12), from which compounds 1 and 2 were derived (13,15). The thiopeptides were more potent than the marketed antibiotics against the E. faecalis and S. aureus reference strains tested.…”

Section: Resultssupporting

confidence: 86%

“…To address the need for novel chemical classes with new mechanisms of action and no cross-resistance with existing drugs, we screened a library of synthetic compounds, pure natural products and microbial extracts for antibacterial activity against the methicillin-and glycopeptide-resistant S. aureus strain Mu50 (11,15,23). The thiopeptide GE2270 A, a known inhibitor of bacterial elongation factor Tu (1,16), was identified as an antibacterial hit (Ͼ50% growth inhibition at 4 M) in the assay (20).…”

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confidence: 99%

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In Vitro and In Vivo Activities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

Leeds

LaMarche²,

Brewer³

et al. 2011

Antimicrob Agents Chemother

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Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC 90 < 0.25 g/ml) but weaker against the streptococci (MIC 90 > 4 g/ml).

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Section: Resultssupporting

confidence: 86%

mentioning

confidence: 99%

In Vitro and In Vivo Activities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

Leeds

LaMarche²,

Brewer³

et al. 2011

Antimicrob Agents Chemother

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“…The 4‐aminothiazolyl moiety was chosen as a starting point and a wide variety of amines and acids linked via different spacers were synthesized 83, 84, 85. Guided by co‐crystal structures with EF‐Tu, this search led to the discovery of two potent analogues with cyclohexylcarboxylic acid side chains residing in proximity to the Arg223 residue of EF‐Tu.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…The oxazolidine-linked L-Ser-L-Pro-NH 2 side chain of GE2270A undergoes, on acid treatment, an N-O acyl shift, forming a diketopiperazine ester that can be easily removed by mild basic treatment (19,20). The newly formed carboxylic acid 2 can thus be effectively amidated, as for example with 4-amino-N-benzylpiperidine, to afford NAI003 (Fig.…”

Section: Synthesis Of Nai003mentioning

confidence: 99%

A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes

Fabbretti

Gaspari³

et al. 2015

Antimicrob Agents Chemother

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A chemical derivative of the thiopeptide GE2270A, designated NAI003, was found to possess a substantially reduced antibacterial spectrum in comparison to the parent compound, being active against just a few Gram-positive bacteria. In particular, NAI003 retained low MICs against all tested isolates of Propionibacterium acnes and, to a lesser extent, against Enterococcus faecalis. Furthermore, NAI003 showed a time-and dose-dependent killing of both a clindamycin-resistant and a clindamycinsensitive P. acnes isolate. Gel shift experiments indicated that, like the parent compound, NAI003 retained the ability to bind to elongation factors Tu (EF-Tus) derived from Escherichia coli, E. faecalis, or P. acnes, albeit with reduced efficiency. In contrast, EF-Tus derived from the NAI003-insensitive Staphylococcus aureus or Streptococcus pyogenes did not bind this compound. These results were confirmed by in vitro studies using a hybrid translation system, which indicated that NAI003 can inhibit most efficiently protein synthesis driven by the P. acnes EF-Tu. P. acnes mutants resistant to NAI003 were isolated by direct plating. With one exception, all analyzed strains carried mutations in the tuf gene, encoding EF-Tu. Because of its selective effect on P. acnes in comparison to resident skin flora, NAI003 represents a promising candidate for the topical treatment of acne, which has already completed a phase 1 clinical study.

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4-Aminothiazolyl Analogues of GE2270 A: Antibacterial Lead Finding

Cited by 35 publications

References 24 publications

In Vitro and In Vivo Activities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

In Vitro and In Vivo Activities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

Targeting Antibiotic Resistance

A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes

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