Water-Soluble Pleuromutilin Derivative with Excellent in Vitro and in Vivo Antibacterial Activity against Gram-Positive Pathogens

Hirokawa, Yoshimi; Kinoshita, Hironori; Tanaka, Tomoyuki; Nakata, Katsuhisa; Kitadai, Noriyuki; Fujimoto, Koichi; Kashimoto, Shigeki; Kojima, Tsuyoshi; Kato, Shiro

doi:10.1021/jm8000136

Cited by 31 publications

(19 citation statements)

References 9 publications

(19 reference statements)

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“…The team of Hirokawa designed and prepared a series of compounds bearing a purine ring as a polar and water-solubilizing group and a 4-piperidinethio moiety and a piperazine ring as central spacers, and they evaluated the in vitro and in vivo activities of the compounds, several of which exhibited strong in vivo activity. [12][13][14]22) The group of Wang synthesized a series of valnemulin analogs. Several analogs exhibited good in vitro activity.…”

Section: -21)mentioning

confidence: 99%

Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives

Liu

Xiao

Zhang

et al. 2015

Biological & Pharmaceutical Bulletin

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In this study we describe the design, synthesis, and antibacterial activity of novel pleuromutilin analogs. A series of new compounds containing piperazine and alkylamino or arylamino groups was synthesized. The new compounds were characterized via 1 H-NMR, 13 C-NMR, Fourier transform (FT)-IR and MS, and were further evaluated for their in vitro activity against seven Gram-positive, and one Gram-negative, pathogens. Antibacterial data revealed that all compounds exhibited moderate to good antibacterial activities against sensitive Gram-positive pathogens. Specifically, 9d displayed the best activity: its activity to Staphylococcus aureus (ATCC25923) is 0.125 µg/mL, which is equal to the control compound tiamulin. The antibacterial activities of 9d to Streptococcus suis (minimum inhibitory concentration (MIC) of 2 µg/mL), Streptococcus agalactiae (MIC of 0.5 µg/mL), and Streptococcus dysgalactiae (MIC of 0.5 µg/mL) were also excellent compared with the control drug erythromycin (MIC of >128 µg/mL). The binding modes of these compounds with active sites were calculated using the programs of Molecular Operating Environment (MOE) and Pymol.Key words pleuromutilin; antibacterial activity; design; synthesis; Gram positive Although countless lives of people have been saved since the discovery of antibiotics, the problem with bacterial resistance to many antibiotics, especially cross resistance, has been increasing. Therefore, we need to identify and develop new antibacterial agents with novel mechanisms of action against bacterial strains. 1) Thus far, the use of natural products or semisynthetic derivatives of natural products has been the most successful method of developing new antibiotics.Pleuromutilin (1) ( Fig. 1) was first isolated in 1951 from basidiomycetes Pleurotus and P. passeckerianus, and it exhibits modest in vitro activity against Gram-positive pathogens and mycoplasmas [2][3][4] and weaker in vivo activity. Pleuromutilin has an unusual 5-6-8 tricyclic diterpene structure. This structure was reported by Birch et al. in the 1960 s and was then confirmed via X-ray crystal diffraction technology. 5) Further studies have shown that this class of antibiotics interferes with bacterial protein synthesis via a specific interaction with Domain V of the 23S ribosomal RNA (rRNA) of the 50S bacterial ribosome subunit, Cross-resistance with other antimicrobial classes is uncommon.6,7) Specifically, these compounds could bind to the peptidyl transferase center (PTC) of the ribosomal 50S subunit with its tricyclic mutilin core positioned in a tight pocket at the A-tRNA binding site, which subsequently prevents the correct positioning of the CCA ends of tRNAs for peptide transfer.7-9) All of the aforementioned interactions involve prokaryotic ribosomes and not eukaryotic proteins and mammalian ribosomes. 4) Based on the structure-activity relationship (SAR) studies, we know that the 5-6-8 tricyclic core is essential for bioactivity, and the carbonyl of C3 and the hydroxyl of C11 are the key groups of antibacterial acti...

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Section: -21)mentioning

confidence: 99%

Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives

Liu

Xiao

Zhang

et al. 2015

Biological & Pharmaceutical Bulletin

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“…These pleuromutilin analogues showed good solubility in water and excellent antibacterial activity in vitro and in vivo. 13 In our previous research, some pleuromutilin derivatives containing substituent pyrazole rings (Fig. 1, 7) 16 and phenyl rings ( Fig.…”

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confidence: 87%

“…6 Based on these structure-activity relationships (SARs), large numbers of pleuromutilin derivatives had been designed and synthesised. [7][8][9][10][11][12][13][14][15] As a result, tiamulin ( Fig. 1, 2) 7 and valnemulin ( Fig.…”

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confidence: 99%

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Synthesis and Antibacterial Activities of Pleuromutilin Derivatives with Thiazole-5-Carboxamide and Thioether Moiety

Wang

Dai

Zhu

et al. 2011

Journal of Chemical Research

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Seven novel pleuromutilin derivatives with thiazole-5-carboxamide and thioether moiety in the C 14 side chain were designed and synthesised. The antibacterial activities of the target compounds were tested via agar-well diffusion method in vitro. The results showed that three target compounds still had antibacterial activity against Staphylococcus aureus ATCC26112 and Staphylococcus aureus SC at a low concentration of 0.05 µg mL −1 .

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“…BC-3781 (Nabriva Therapeutics)). 10,11,12 The majority of pleuromutilin derivatives reported to date displays a spectrum of activity focused against Gram-positive bacteria, 13,14,15,16,17,18,19,20,21 and very few analogues have been demonstrated to exhibit antimycobacterial activity. Long et.…”

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confidence: 99%

An antimycobacterial pleuromutilin analogue effective against dormant bacilli

Lemieux

Siricilla

Mitachi

et al. 2018

Bioorganic & Medicinal Chemistry

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Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2xMIC concentrations. Pharmacokinetic studies indicate that 1 has an oral bioavailability with an average F-value of 27.6%. Pleuromutilin may have the potential to be developed into an orally administered anti-TB drug.

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Water-Soluble Pleuromutilin Derivative with Excellent in Vitro and in Vivo Antibacterial Activity against Gram-Positive Pathogens

Cited by 31 publications

References 9 publications

Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives

Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives

Synthesis and Antibacterial Activities of Pleuromutilin Derivatives with Thiazole-5-Carboxamide and Thioether Moiety

An antimycobacterial pleuromutilin analogue effective against dormant bacilli

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