Chemical modification of capuramycins to enhance antibacterial activity

Bogatcheva, Elena; Dubuisson, Tia; Protopopova, Marina; Einck, Leo; Nacy, Carol A.; Reddy, Venkata M.

doi:10.1093/jac/dkq495

Cited by 39 publications

(20 citation statements)

References 30 publications

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“…1a) 5-8 . MraY-targeted natural products have gained attention because of their in vivo efficacy against pathogenic bacteria including M. tuberculosis, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) 6,9-12 . Despite their promise, no antibacterial natural products that target MraY have been developed for clinical use, in part due to a lack of structural information on MraY catalysis and inhibition.…”

mentioning

confidence: 99%

Structural insights into inhibition of lipid I production in bacterial cell wall synthesis

Chung

Mashalidis

Tanino

et al. 2016

Nature

105

156

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Summary Antibiotic-resistant bacterial infection is a serious threat to public health. Peptidoglycan biosynthesis is a well-established target for antibiotic development. MraY (phospho-MurNAc-pentapeptide translocase) catalyzes the first and an essential membrane step of peptidoglycan biosynthesis. It is considered a very promising target for the development of new antibiotics, as many naturally occuring nucleoside inhibitors with antibacterial activity target this enzyme1-4. However, antibiotics targeting MraY have not been developed for clinical use mainly due to a lack of structural insight into inhibition of this enzyme. Here we present the crystal structure of MraY from Aquifex aeolicus (MraYAA) in complex with its naturally occurring inhibitor, muraymycin D2 (MD2). Upon binding MD2, MraYAA undergoes remarkably large conformational rearrangements near the active site, which lead to the formation of a nucleoside-binding pocket and a peptide-binding site. MD2 binds the nucleoside-binding pocket like a two-pronged plug inserting into a socket. Additional interactions it makes in the adjacent peptide-binding site anchor MD2 to and enhance its affinity for MraYAA. Surprisingly, MD2 does not interact with three acidic residues or the Mg2+ cofactor required for catalysis, suggesting that MD2 binds to MraYAA in a manner that overlaps with, but is distinct from its natural substrate, UDP-MurNAc-pentapeptide. We have deciphered the chemical logic of MD2 binding to MraYAA, including how it avoids the need for pyrophosphate and sugar moieties, which are essential features for substrate binding. The conformational plasticity of MraY could be the reason that it is the target of many structurally distinct inhibitors. These findings can inform the design of new inhibitors targeting MraY as well as its paralogs, WecA and TarO.

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mentioning

confidence: 99%

Structural insights into inhibition of lipid I production in bacterial cell wall synthesis

Chung

Mashalidis

Tanino

et al. 2016

Nature

105

156

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“…In murine model of tuberculosis, it has been shown that the treatment of mice with SQ609 is able to prevent weight loss in these mice. Furthermore, SQ609 has a prolonged therapeutic effect, extended by two weeks after termination of treatment, suggesting that SQ609 is well tolerated by mice and that this compound is not eliminated immediately following cessation of treatment [62]. SQ609 has good water solubility and has an antimycobacterial activity better than that of TB standard of care (1 --2 log 10 ) when administered in combination with INH, RIF, and PZA in murine models of TB.…”

Section: Sq609mentioning

confidence: 99%

“…In the same study, it was shown that treatment of mice for five weeks at 100 mg/kg with SQ641-TPGS micelles administered intraperitoneally reduced log 10 numbers of CFU in lungs from 8.09 to 6.15, while intravenous delivery of SQ641-TPGS micelles at 50 mg/kg, two times per week for four weeks decreased CFU numbers in lungs by 2.08 log [66]. More recently, a study involving murine macrophages infected with M. tuberculosis H37Rv strain has shown that acylation of SQ641 with amino undecanoic acid improves its intracellular bactericidal activity against M. tuberculosis H37Rv strain [62], suggesting that the modified version of SQ641 would be better than its original form for TB treatment.…”

Section: Sq641mentioning

confidence: 99%

Antimycobacterial drugs currently in Phase II clinical trials and preclinical phase for tuberculosis treatment

Engohang‐Ndong¹

2012

Expert Opinion on Investigational Drugs

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“…As a result, it has poor intracellular and in vivo activity (11,12). To overcome these deficiencies, we earlier developed ␣-tocopheryl polyethylene glycol 1000 succinate (TPGS) soluble and micellar formulations of SQ641 (13,14).…”

mentioning

confidence: 99%

“…SQ641 was synthesized at Sequella, Inc., as described previously (7,12). INH, EMB, rifampin (RIF), and pyrazinamide (PZA) were purchased from Sigma-Aldrich, St. Louis, MO.…”

mentioning

confidence: 99%

Therapeutic Efficacy of SQ641-NE against Mycobacterium tuberculosis

Никоненко

Reddy

Bogatcheva

et al. 2014

Antimicrob Agents Chemother

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A phospholipid-based nanoemulsion formulation of SQ641 (SQ641-NE) was active against intracellular Mycobacterium tuberculosis in J774A.1 mouse macrophages, although SQ641 by itself was not. Intravenous (i.v.) SQ641-NE was cleared from circulation and reached peak concentrations in lung and spleen in 1 h. In a murine tuberculosis (TB) model, 8 i.v. doses of SQ641-NE at 100 mg/kg of body weight over 4 weeks caused a 1.73 log 10 CFU reduction of M. tuberculosis in spleen and were generally bacteriostatic in lungs. C apuramycin (CM) is a novel nucleoside antibiotic that specifically inhibits biosynthesis of peptidoglycan (PG) by blocking the translocase I (TL1) enzyme (1-4). SQ641 is the most potent analogue in this series for in vitro activity against several species of mycobacteria (5-8). SQ641 is rapidly bactericidal for Mycobacterium tuberculosis and has a lasting postantibiotic effect (PAE). It is synergistic with ethambutol (EMB) and additive with isoniazid (INH) (8-10).Despite its excellent in vitro activity, SQ641 possesses several deficiencies that impair its therapeutic efficacy against tuberculosis (TB): it is poorly soluble in water and is not absorbed orally. As a result, it has poor intracellular and in vivo activity (11,12). To overcome these deficiencies, we earlier developed ␣-tocopheryl polyethylene glycol 1000 succinate (TPGS) soluble and micellar formulations of SQ641 (13,14). Even though these formulations demonstrated better intracellular and in vivo efficacy, both formulations suffer from low drug loading and are thus unsuitable for human use: too large a volume is needed to see efficacy. We developed a phospholipid-based nanoemulsion formulation that accommodates higher drug loading and is compatible for human use.Animal experiments were performed by Sequella personnel at BIOQUAL, Inc. (Rockville, MD), by Institutional Agreement and were performed according to guidelines of U.S. Government Policy on Care and Use of Laboratory Animals in biomedical research (assurance A2796.02).SQ641 was synthesized at Sequella, Inc., as described previously (7, 12). INH, EMB, rifampin (RIF), and pyrazinamide (PZA) were purchased from Sigma-Aldrich, St. Louis, MO. A phospholipid-based nanoemulsion formulation of SQ641 (SQ641-NE) was prepared in phospholipid Phosal 53 MCT (Lipoid GmbH, Ludwigshafen, Germany) using TPGS as the emulsifier and characterized as described previously (15). Intracellular activity of the compounds was determined by using the M. tuberculosis luciferase reporter H37Rv-pSMT1 strain and J77A.1 mouse macrophage cell line (14,16,17). In vivo efficacy of SQ641-NE was tested in a mouse model of TB infection (11) using a mousepassaged M. tuberculosis H37Rv (Pasteur) strain (kind gift of J. Marshal). C57BL/6 female mice (Charles River Laboratories, Raleigh, NC) were infected intravenously (i.v.) with 10 5 CFU H37Rv, and therapy was initiated 3 weeks later. SQ641-NE was administered i.v. 2 times/week or intraperitoneally (i.p.) 5 times/week for 4 weeks; INH was administered orally (p.o.) 5 times/...

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Chemical modification of capuramycins to enhance antibacterial activity

Abstract: Conjugation of capuramycin analogues with AUA or DEC enhanced in vitro activity, extended the spectrum of activity in Gram-positive bacteria and increased intracellular activity against H37Rv.

Cited by 39 publications

References 30 publications

Structural insights into inhibition of lipid I production in bacterial cell wall synthesis

Structural insights into inhibition of lipid I production in bacterial cell wall synthesis

Antimycobacterial drugs currently in Phase II clinical trials and preclinical phase for tuberculosis treatment

Therapeutic Efficacy of SQ641-NE against Mycobacterium tuberculosis

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