Structure of Tebipenem
CAS No.: 161715-21-5
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Tebipenem is a broad-spectrum antibiotic, from the carbapenem subgroup of β-lactam antibiotics.
Synonyms: LJC 11036
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Beta-lactam combination treatment overcomes rifampicin resistance in Mycobacterium tuberculosis
Quan, Diana H ; Wang, Trixie ; Martinez, Elena ; Kim, Hanna Y ; Sintchenko, Vitali ; Britton, Warwick J , et al.
Abstract: The significant global impact of tuberculosis (TB) on human health is exacerbated by the increasing prevalence of multidrug resistant tuberculosis (MDR-TB) and the challenges of novel drug discovery for the treatment of drug-susceptible and drug-resistant strains of M. tuberculosis. Rifampicin is a key first-line TB drug and rifampicin resistance is a major obstacle to treating MDR-TB. Utilising existing antimicrobial drugs to supplement combination therapy and overcome rifampicin resistance is a promising solution due to their widespread availability and proven clinical safety profile. Therefore, this study aimed to explore the feasibility of using beta-lactam/beta-lactamase inhibitor combinations with rifampicin to inhibit the growth of multidrug-resistant M. tuberculosis. Based on inhibitory concentration (IC), oral bioavailability, pricing, commercial availability, five beta-lactams and the beta-lactamase inhibitor, clavulanate, were selected for testing. These were combined with rifampicin for in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit (CFU) enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index (DRI). The combination of tebipenem-clavulanate/rifampicin and cephradine-clavulanate/rifampicin were found to be synergistic and highly effective against clinical isolates of MDR-TB, overcoming rifampicin resistance in vitro. Beta-lactam synergy may provide viable combination therapies with rifampicin to address the issue of drug resistance in TB.
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Keywords: Tuberculosis ; Drug resistance ; Beta-lactam ; Beta-lactamase inhibitor
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Synergistic oral beta-lactam combinations for treating tuberculosis
Quan, Diana H ; Wang, Trixie ; Martinez, Elena ; Kim, Hannah Y ; Sintchenko, Vitali ; Britton, Warwick J , et al.
Abstract: Background: The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta- lactams in combination with a beta-lactamase inhibitor, which have been underutilised in TB treatment to date. Methods: Based on inhibitory concentration, oral bioavailability and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second- line TB drugs (moxifloxacin, levofloxacin and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit (CFU) enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index (DRI). Results: The order of activity of beta-lactams was cefadroxil > tebipenem > cephradine > cephalexin > cefdinir > penicillin V > flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin and cefdinir/moxifloxacin. Conclusions: Beta-lactam synergy may provide viable combination therapies for the treatment of TB.
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Keywords: tuberculosis, beta-lactam, synergy, combination therapy
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Sayed, Alaa R. M. ; Shah, Nirav R. ; Basso, Kari B. ; Kamat, Manasi ; Jiao, Yuanyuan ; Moya, Bartolome , et al.
Abstract: Mycobacterium abscessus causes serious infections that often require over 18 mo of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clin. have had low success rates and high rates of toxicities. With β-lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving the treatment of M. abscessus infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different β-lactams in M. abscessus. We determined the preferred PBP targets of 13 β-lactams and 2 β-lactamase inhibitors in two M. abscessus strains and identified PBP sequences by proteomics. The Bocillin FL binding assay was used to determine the β-lactam concentrations that half-maximally inhibited Bocillin binding (50% inhibitory concentrations [IC50s]). Principal component anal. identified four clusters of PBP occupancy patterns. Carbapenems inactivated all PBPs at low concentrations (0.016 to 0.5 mg/L) (cluster 1). Cephalosporins (cluster 2) inactivated PonA2, PonA1, and PbpA at low (0.031 to 1 mg/L) (ceftriaxone and cefotaxime) or intermediate (0.35 to 16 mg/L) (ceftazidime and cefoxitin) concentrations Sulbactam, aztreonam, carumonam, mecillinam, and avibactam (cluster 3) inactivated the same PBPs as cephalosporins but required higher concentrations Other penicillins (cluster 4) specifically targeted PbpA at 2 to 16 mg/L. Carbapenems, ceftriaxone, and cefotaxime were the most promising β-lactams since they inactivated most or all PBPs at clin. relevant concentrations These first PBP occupancy patterns in M. abscessus provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with β-lactams.
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Keywords: Mycobacterium abscessus ; PbpA ; PonA1 ; PonA2 ; beta-lactams ; cell wall biosynthesis ; drug-resistant bacteria ; penicillin-binding proteins ; principal component analysis ; receptor binding
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CAS No. : | 161715-21-5 |
Formula : | C16H21N3O4S2 |
M.W : | 383.49 |
SMILES Code : | O=C(C(N12)=C(SC3CN(C4=NCCS4)C3)[C@H](C)[C@]2([H])[C@@H]([C@H](O)C)C1=O)O |
Synonyms : |
LJC 11036
|
MDL No. : | MFCD00936545 |
InChI Key : | GXXLUDOKHXEFBQ-YJFSRANCSA-N |
Pubchem ID : | 9800194 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
In Vitro:
Concentration | Treated Time | Description | References |
MRSA 67-0 | 8–16 μg/mL | 10 minutes | Evaluate SPR859 binding to MRSA PBP 2a, results showed SPR859 is superior to meropenem | Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02181-18 |
Staphylococcus aureus ATCC 29213 | 0.03–0.12 μg/mL | 10 minutes | Evaluate SPR859 binding to S. aureus PBPs, results showed SPR859 has low IC50 values for PBP 1 and PBP 4 | Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02181-18 |
Pseudomonas aeruginosa ATCC 27853 | 2 μg/mL | 10 minutes | Evaluate SPR859 binding to P. aeruginosa PBPs, results showed SPR859 has high binding to PBP 2 and PBP 3 | Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02181-18 |
Klebsiella pneumoniae ATCC 13883 | 0.06–0.12 μg/mL | 10 minutes | Evaluate SPR859 binding to K. pneumoniae PBPs, results showed SPR859 primarily binds PBP 2 | Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02181-18 |
Escherichia coli K-12 | 0.015–0.03 μg/mL | 10 minutes | Evaluate SPR859 binding to E. coli PBPs, results showed SPR859 binds to all PBPs, especially PBP 2 | Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02181-18 |
Genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) | 0.063 μg/mL | 18 to 24 hours | Evaluate the antibacterial activity of Tebipenem against gPRSP, showing its MIC90 was significantly lower than other reference antibiotics. | Antimicrob Agents Chemother. 2005 Mar;49(3):889-94 |
Genotypic penicillin-intermediate Streptococcus pneumoniae (gPISP) | 0.004 μg/mL | 18 to 24 hours | Evaluate the antibacterial activity of Tebipenem against gPISP, showing its MIC90 was significantly lower than other reference antibiotics. | Antimicrob Agents Chemother. 2005 Mar;49(3):889-94 |
Penicillin-susceptible Streptococcus pneumoniae (PSSP) | 0.002 μg/mL (MIC90) | 18 to 24 hours | Evaluate the antibacterial activity of Tebipenem against PSSP, showing its MIC90 was significantly lower than other reference antibiotics. | Antimicrob Agents Chemother. 2005 Mar;49(3):889-94 |
Klebsiella pneumoniae | 0.125 mg/L (MIC90) | 18-20 hours | To assess the in vitro susceptibility of tebipenem against third-generation cephalosporin-resistant K. pneumoniae, showing stability against ESBL and AmpC enzymes | JAC Antimicrob Resist. 2022 Sep 30;4(5):dlac105 |
Escherichia coli | 0.03 mg/L (MIC90) | 18-20 hours | To assess the in vitro susceptibility of tebipenem against third-generation cephalosporin-resistant E. coli, showing stability against ESBL and AmpC enzymes | JAC Antimicrob Resist. 2022 Sep 30;4(5):dlac105 |
Haemophilus influenzae | 0.008–1 μg/mL | 20 hours | To evaluate the antibacterial and bactericidal activities of Tebipenem against Haemophilus influenzae. Results showed that the MIC90 of Tebipenem was lower than those of other oral antibiotics except for cefditoren, and it exhibited excellent bactericidal activity against BLNAR strains. | Antimicrob Agents Chemother. 2010 Sep;54(9):3970-3 |
Salmonella Paratyphi A | 4×MIC | 24 hours | To evaluate the bactericidal effect of tebipenem against Salmonella Paratyphi A, showing complete killing at 4×MIC after 24 hours. | J Antimicrob Chemother. 2021 Nov 12;76(12):3197-3200 |
Mycobacterium abscessus clinical isolates | 0.25–256 µg/mL | 3-14 days | To evaluate the in vitro effects of tebipenem in combination with xeruborbactam against Mycobacterium abscessus. Results showed that xeruborbactam lowered the MIC90 of tebipenem by 5 dilutions, and the number of susceptible isolates increased from 1/43 (2%) to 43/43 (100%). | Microbiol Spectr. 2024 Jul 2;12(7):e0008424 |
Mycobacterium tuberculosis H37Rv | 0.25 µg/mL | 5 days | Evaluate the bactericidal effect of Tebipenem in combination with cefuroxime, showing significant potentiation of killing activity | Antimicrob Agents Chemother. 2024 Jun 5;68(6):e0003424 |
E. coli 13319 | 0.015 mg/L | 7 days | Evaluate the antibacterial activity of Tebipenem against ESBL-producing E. coli, showing failure to maintain reduction in bacterial burden. | Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0090822 |
E. coli 998822 | 0.03 mg/L | 7 days | Evaluate the antibacterial activity of Tebipenem against ESBL-producing E. coli, showing bacterial densities reduced to the level of detection. | Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0090822 |
E. coli 1033345 | 0.06 mg/L | 7 days | Evaluate the antibacterial activity of Tebipenem against ESBL-producing E. coli, showing bacterial densities reduced to the level of detection. | Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0090822 |
E. coli 4643 | 0.008 mg/L | 7 days | Evaluate the antibacterial activity of Tebipenem against ESBL-producing E. coli, showing a reduction in bacterial burden by 2.5 to 3 log10 CFU. | Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0090822 |
E. coli NCTC 13441 | 0.015 mg/L | 7 days | Evaluate the antibacterial activity of Tebipenem against ESBL-producing E. coli, showing a reduction in bacterial burden by 2.5 to 3 log10 CFU. | Antimicrob Agents Chemother. 2023 Mar 16;67(3):e0090822 |
Mycobacterium tuberculosis H37Rv | 0.4 µg/mL | 7 days | Evaluate the growth inhibitory effect of Tebipenem on Mycobacterium tuberculosis H37Rv | Antimicrob Agents Chemother. 2024 Jun 5;68(6):e0003424 |
Salmonella Typhi | 2-4×MIC | 8-24 hours | To evaluate the bactericidal effect of tebipenem against XDR and non-XDR Salmonella Typhi, showing complete killing within 8-24 hours at 2-4×MIC. | J Antimicrob Chemother. 2021 Nov 12;76(12):3197-3200 |
Burkholderia pseudomallei | 1 to 4 mg/mL | Evaluate in vitro activity of Tebipenem against B. pseudomallei | Antimicrob Agents Chemother. 2021 May 1;65(5):e02385-20 | |
Burkholderia mallei | 0.25 to 1 mg/mL | Evaluate in vitro activity of Tebipenem against B. mallei | Antimicrob Agents Chemother. 2021 May 1;65(5):e02385-20 | |
Yersinia pestis | 0.0005 to 0.03 mg/mL | Evaluate in vitro activity of Tebipenem against Y. pestis | Antimicrob Agents Chemother. 2021 May 1;65(5):e02385-20 | |
Bacillus anthracis | 0.001 to 0.008 mg/mL | Evaluate in vitro activity of Tebipenem against B. anthracis | Antimicrob Agents Chemother. 2021 May 1;65(5):e02385-20 |
In Vivo:
Administration | Dosage | Frequency | Description | References |
Mice | B. anthracis infection model | Oral | 33.3 mg/kg | Every 8 hours for 14 days | Evaluate in vivo efficacy of Tebipenem against B. anthracis infection, survival rates were 75% and 73% | Antimicrob Agents Chemother. 2021 May 1;65(5):e02385-20 |
NOD SCID mice | M. abscessus lung infection model | Oral | 400 mg/kg TBP-PI + 200 mg/kg AVI-ARX | Twice daily for first 6 days, then once daily for next 4 days (total 10 days) | Evaluate efficacy of oral TBP-PI/AVI-ARX against M. abscessus lung infection; achieved ~10-fold reduction in lung CFU. | Antimicrob Agents Chemother. 2023 Feb 16;67(2):e0145922 |
Female C57 mice | Shigella infection model | Oral | 50 mg/kg | 2 doses, 14 hours apart | To evaluate the efficacy of Tebipenem pivoxil in a mouse model of Shigella infection. Results showed that 50 mg/kg oral Tebipenem pivoxil significantly reduced bacterial load in the small and large intestines. | Elife. 2022 Mar 15;11:e69798 |
Mice | Sepsis mouse models | Oral | 50 mg/kg and 100 mg/kg | Single administration, observed for 168 hours | To evaluate the protective effect of Tebipenem Pivoxil tablet on sepsis mice, the results showed that it significantly increased the survival rate of mice, and the effect was better than that of meropenem and Tebipenem Pivoxil granules. | Molecules. 2016 Jan 6;21(1):62 |
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1mg | 5mg | 10mg |
1 mM 5 mM 10 mM |
2.61mL 0.52mL 0.26mL |
13.04mL 2.61mL 1.30mL |
26.08mL 5.22mL 2.61mL |