A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking

Zhang, Zhe; Zhang, Zhaosheng; Wang, Xiao; Xi, Gaolei; Jin, Zhen; Tang, You‐Zhi

doi:10.1080/14756366.2021.1977931

Cited by 11 publications

(7 citation statements)

References 37 publications

(37 reference statements)

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“…Because these antibiotics have the same mode of action involving the inhibition of protein synthesis, − measuring the IC 50 using the E. coli S30 extract system would provide IC 50 values under membrane-free conditions (Figures S14 and S15). If an antibiotic passes through the OM freely by 1403, its IC 50 value should correlate with its MIC value with 1403.…”

Section: Resultsmentioning

confidence: 99%

Proline-Hinged α-Helical Peptides Sensitize Gram-Positive Antibiotics, Expanding Their Physicochemical Properties to Be Used as Gram-Negative Antibiotics

Choi,

Choe,

Kook

et al. 2023

J. Med. Chem.

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The outer membrane (OM) of Gram-negative bacteria is the most difficult obstacle for small-molecule antibiotics to reach their targets in the cytosol. The molecular features of Gram-negative antibiotics required for passing through the OM are that they should be positively charged rather than neutral, flat rather than globular, less flexible, or more increased amphiphilic moment. Because of these specific molecular characteristics, developing Gram-negative antibiotics is difficult. We focused on sensitizer peptides to facilitate the passage of hydrophobic Grampositive antibiotics through the OM. We explored ways of improving the sensitizing ability of proline-hinged α-helical peptides by adjusting their length, hydrophobicity, and N-terminal groups. A novel peptide, 1403, improves the potentiation of rifampicin in vitro and in vivo and potentiates most Gram-positive antibiotics. The "sensitizer" approach is more plausible than those that rely on conventional drug discovery methods concerning drug development costs and the development of drug resistance.

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Section: Resultsmentioning

confidence: 99%

Proline-Hinged α-Helical Peptides Sensitize Gram-Positive Antibiotics, Expanding Their Physicochemical Properties to Be Used as Gram-Negative Antibiotics

Choi,

Choe,

Kook

et al. 2023

J. Med. Chem.

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“…White powder; yield: 42.5%; mp: 99.9− 102.8 °C; 1 H NMR (400 MHz, CDCl (24). White powder; yield: 39.8%; mp: 89.4−93.2 °C; 1 H NMR (400 MHz, CDCl (25). White powder; yield: 31.6%; mp: 106.8− 108.7 °C; 1 H NMR (400 MHz, CDCl (26) Hz, 1H, H13), 1.15 (s, 3H, H18), 1.10 (dd, J = 13.6, 4.4 Hz, 1H, H8), 0.87 (d, J = 7.2 Hz, 3H, H17), 0.70 (d, J = 6.8 Hz, 3H, H16); 13 C NMR (101 MHz, CDCl 3 ): δ(ppm) 216.9 (C3), 169.0 (C21), 168.8, 154.5, 139.0 (C19), 136.9, 129.1, 129.0, 119.3, 117.2 (C20), 74.6 (C11), 72.9, 68.5 (C14), 59.6 (C22), 58.1 (C4), 52.6, 52.3, 52.2, 50.6, 48.0, 45.4 (C9), 45.0 (C13), 44.2, 43.9 (C12), 41.7 (C5), 36.7 (C6), 36.0 (C10), 34.4 (C2), 30.4 (C8), 26.8 (C7), 26.4 (C18), 24.8 (C1), 16 H6, H7, H1, OH), 1.42 (s, 3H, H15), 1.35 (dd, J = 14.4, 3.2 Hz 1H, H7), 1.27 (d, J = 16.0 Hz, 1H, H13), 1.15 (s, 3H, H18), 1.10 (dd, J = 13.6, 4.4 Hz, 1H, H8), 0.87 (d, J = 6.8 Hz, 3H, H17), 0.70 (d, J = 6.8 Hz, 3H, H16); 13 C NMR (101 MHz, CDCl 3 ): δ(ppm) 216.9 (C3), 169.0 (C21), 168.8, 154.4, 139.0 (C19), 137.4, 131.9, 119.6, 117.2 (C20), 116.7, 74.6 (C11), 72.9, 68.5 (C14), 59.6 (C22), 58.1 (C4), 52.6, 52.3, 52.2, 50.6, 47.9, 45.4 (C9), 45.0 (C13), 44.2, 43.9 (C12), 41.7 (C5), 36.7 (C6), 36.0 (C10), 34.4 (C2), 30 (30).…”

Section: Synthesis Of 22-(piperazine-1-yl)-22-deoxypleuromutilin (14)mentioning

confidence: 99%

“…From the four marketed pleuromutilin derivatives, it can be seen that the introduction of an aliphatic thioether linker is beneficial for enhancing activity, so mercaptoethylamine was chosen. In addition, many compounds containing nitrogen structure at the C-14 side chain have also been reported to have good activities recently, , and a more water-soluble structure piperazine was used as the connecting unit as well. In order to simplify the linker and ensure the inclusion of heteroatom, a nitrogen atom directly connected was adopted additionally.…”

mentioning

confidence: 99%

Synthesis and Biological Activities of Oxazolidinone Pleuromutilin Derivatives as a Potent Anti-MRSA Agent

Xia,

Li,

et al. 2023

ACS Infect. Dis.

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A series of pleuromutilin derivatives containing an oxazolidinone skeleton were synthesized and evaluated in vitro and in vivo as antibacterial agents. Most of the synthesized derivatives exhibited potent antibacterial activities against three strains of Staphylococcus aureus (including MRSA ATCC 33591, MRSA ATCC 43300, and MSSA ATCC 29213) and two strains of Staphylococcus epidermidis (including MRSE ATCC 51625 and MSSE ATCC 12228). Compound 28 was the most active antibacterial agent in vitro (MIC = 0.008−0.125 μg•mL −1 ) and exhibited a significant bactericidal effect, low cytotoxicity, and weak inhibition (IC 50 = 20.66 μmol•L −1 ) for CYP3A4, as well as exhibited less possibility to cause bacterial resistance. Furthermore, in vivo activities indicated that the compound was effective in reducing MRSA load in a murine thigh infection model. Moreover, it clearly facilitated the healing of MRSA skin infection and inhibited the secretion of the TNF-α, IL-6, and MCP-1 inflammatory factors in serum. These results suggest that oxazolidinone pleuromutilin is a promising therapeutic candidate for drug-resistant bacterial infections.

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“…[1,2] Drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycinresistant Enterococcus (VRE) have emerged as predominant cause of nosocomial infections and can induce a wide spectrum of diseases associated with high morbidity and mortality. [3][4][5][6] Studies have shown that biofilm formation is a common defense mechanism of drug-resistant bacteria, and approximately 65-80 % of bacterial infections are biofilmassociated. [7][8][9] Thus, the development of new antibiofilm agents against S. aureus and E. faecalis has become an urgent task.…”

Section: Introductionmentioning

confidence: 99%

“…Bacteria that can resist clinical antibiotics pose a serious threat to public health around the world and bring a great economic burden to human beings [1,2] . Drug‐resistant bacteria such as methicillin‐resistant Staphylococcus aureus (MRSA) , vancomycin‐resistant Enterococcus (VRE) have emerged as predominant cause of nosocomial infections and can induce a wide spectrum of diseases associated with high morbidity and mortality [3–6] . Studies have shown that biofilm formation is a common defense mechanism of drug‐resistant bacteria, and approximately 65–80 % of bacterial infections are biofilm‐associated [7–9] .…”

Section: Introductionmentioning

confidence: 99%

Development of 2‐Alkyl‐5‐((phenylsulfonyl)oxy)‐1H‐indole‐3‐carboxylate Derivatives as Potential Anti‐Biofilm Agents

Chen

Xiong

et al. 2023

ChemistrySelect

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A series of novel 2-alkyl-5-((phenylsulfonyl)oxy)-1H-indole-3carboxylate derivatives were synthesized and evaluated for their cytotoxicity, antibacterial and anti-biofilm activities. Some of these compounds were able to inhibit biofilm formation of the tested strains with biofilm inhibitory concentration in the range of 12.5-50 μM. The results indicated N-methylpiperazine moiety was the key factor affecting the compound's activity. Compounds 5 l and 5 m with F substituent at the phenyl ring at 5-position of indole ring, presented the most potent biofilm inhibitory activity (more than 90 % inhibition percentage) against E. faecalis 16C51 at biofilm inhibitory concentration (12.5 μM). Furthermore, compounds 5 f and 5 h with Br/CH 3 substituent at the phenyl ring at 1-position of indole ring, showed the greatest biofilm inhibitory activity (more than 85 % inhibition percentage) against MRSA YUSA145 at biofilm inhibitory concentration (12.5 μM).

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A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking

Cited by 11 publications

References 37 publications

Proline-Hinged α-Helical Peptides Sensitize Gram-Positive Antibiotics, Expanding Their Physicochemical Properties to Be Used as Gram-Negative Antibiotics

Proline-Hinged α-Helical Peptides Sensitize Gram-Positive Antibiotics, Expanding Their Physicochemical Properties to Be Used as Gram-Negative Antibiotics

Synthesis and Biological Activities of Oxazolidinone Pleuromutilin Derivatives as a Potent Anti-MRSA Agent

Development of 2‐Alkyl‐5‐((phenylsulfonyl)oxy)‐1H‐indole‐3‐carboxylate Derivatives as Potential Anti‐Biofilm Agents

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