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Effect of TD-1792 against MRSA ATCC 33591 on thigh bacterial burden in mice dosed with various total 24-h doses of TD-1792 (0.03 to 1 mg/kg, SC) administered in one, two, or four divided fractions. The abscissa shows the total 24-h dosage in mg/kg, SC, and the ordinate shows the thigh bacterial burden in log10 CFU/g. Data are expressed as means ± SD (n = 5 to 10).
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TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects
against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1...
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Citations
... Among the two vancomycin-cephalosporin hybrids, TD-1607 4, was discontinued after two phase 1 trials (NCT01791049, NCT01949103) possibly owing to poor tolerability, while TD-1792 1 cleared phase 2 trials for the treatment of Gram-positive complicated skin and soft-tissue infections (Butler and Paterson, 2020;NCT01791049, 2013;NCT01949103, 2013;Long et al., 2008b;Umscheid et al., 2011). Consistent with its in vitro potencies, TD-1792 exhibited strong antibacterial activity in vivo (≥1-log 10 CFU kill) against all Gram-positive strains from methicillin-susceptible S. aureus, methicillin-susceptible S. epidermidis, methicillin-resistant S. epidermidis, penicillin-susceptible S. pneumoniae, S. pyrogenes, MRSA and VISA present in the murine neutropenic thigh infection models investigated by Stryjewski and co-workers (Stryjewski et al., 2012a). TD-1792 is administered intravenously IV), possesses a halflife of 9-13-h, is moderately bound to plasma proteins (~50%) in humans, and is primarily excreted via renal filtration. ...
Antibiotic resistance is a top threat to human health and a priority across the globe. This problematic issue is accompanied by the decline of new antibiotics in the pipeline over the past 30 years. In this context, an urgent need to develop new strategies to combat antimicrobial resistance is in great demand. Lately, among the possible approaches used to deal with antimicrobial resistance is the covalent ligation of two antibiotic pharmacophores that target the bacterial cells through a dissimilar mode of action into a single hybrid molecule, namely hybrid antibiotics. This strategy exhibits several advantages, including better antibacterial activity, overcoming the existing resistance towards individual antibiotics, and may ultimately delay the onset of bacterial resistance. This review sheds light on the latest development of the dual antibiotic hybrids pipeline, their potential mechanisms of action, and challenges in their use.
... In addition, the spectrum activity of 22 was not limited to GV but also active against other pathogens that can cause BV and other anaerobic bacteria. Apart from a few BV-causing bacteria where equivalent activity was displayed, the MIC values of 22 were 100 to 1,000 folds lower than those of metronidazole (Blais et al., 2012); in vivo ED 50 value (Long et al., 2008a); terminal half-life in mice (Hegde et al., 2012). b MIC value (Sader et al., 2014); in vivo ED 50 value (Long et al., 2008a). ...
The tale of abate in antibiotics continued defense mechanisms that chaperone the rise of drug-defying superbugs—on the other hand, the astray in antibacterial drug discovery and development. Our salvation lies in circumventing the genesis of resistance. Considering the competitive advantages of antibacterial chemotherapeutic agents equipped with multiple warheads against resistance, the development of hybrids has rejuvenated. The adoption of antibiotic hybrid paradigm to macrocycles has advanced novel chemical entities to clinical trials. The multi-targeted TD-1792, for instance, retained potent antibacterial activities against multiple strains that are resistant to its constituent, vancomycin. Moreover, the antibiotic conjugation of rifamycins has provided hybrid clinical candidates with desirable efficacy and safety profiles. In 2020, the U.S. FDA has granted an orphan drug designation to TNP-2092, a conjugate of rifamycin and fluoroquinolone, for the treatment of prosthetic joint infections. DSTA4637S is a pioneer antibacterial agent under clinical development and represents a novel class of bacterial therapy, that is, antibody–antibiotic conjugates. DSTA4637S is effective against the notorious persistent S. aureus bacteremia, a revelation of the abracadabra potential of antibiotic hybrid approaches.
... Cefilavancin (TD-1792) (110) was shown to be highly active in relation to Grampositive bacteria, including MRSA, is able to overcome the penicillin resistance in pneumococci and fluoroquinolone resistance in streptococci and has a sufficient stability to the action of β-lactamases [124][125][126]. The drug 110 has passed preclinical trials [127], phase I and II clinical trials (in comparison with vancomycin) for the treatment of complicated skin infections [128] and currently is on Phase III trial as a treatment of G-positive complicated skin and skin structure infections with data expected in 2016 [129]. ...
Introduction:
The increased resistance of glycopeptide based antibiotics has become a serious problem for the chemotherapy of infections triggered by resistant Gram-positive bacteria. This has motivated the urgent sincere efforts to develop potent glycopeptide-based antibiotics in both academy and industry research laboratories. Understanding of the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve the fundamental results. Several hydrophobic glycopeptide analogues active against resistant strains were developed during the last two decades. Three drugs, namely, oritavancin, telavancin and dalbavancin were approved by FDA in 2013-2014. It was found that hydrophobic derivatives act through different mechanisms without binding with the modified target of resistant bacteria. Types: Different types of chemical modifications led to several glycopeptide analogues active against Gram-negative bacteria as advocated by in vitro studies or demonstrating potent antiviral activity in the cell models.
Conclusion:
A new class of glycopeptide antibiotics with potent activity against sensitive and resistant bacterial strains has been recently reported with the aim to overcome the resistance, however, there are a lot of obscure problems in the complete understanding of their mechanisms of actions. In this review, we summarized the achievements of synthetic methods devoted to the construction of new polycyclic glycopeptide antibiotics and described the studies related to their mechanism of actions.
... However, some examples of conjugated antibiotics can already be found under advanced clinical trials or approved for therapy by pharmaceutical regulatory agencies. Namely, TD-1792 which is a glycopeptide-cephalosporin heterodimer antibiotic currently under phase III clinical trials [83,84] and several vaccines that conjugate carrier proteins and glycosyl receptors of bacteria cell capsule, mainly through reductive amination (such as Menactra ® , MenHibrix ® , Menveo ® , Prevnar ® , Synflorix ® , Prevnar13 ® ), that are presently used in prophylactic therapy [85][86][87]. ...
Introduction Drug conjugates are trend topics in Chemical Biology. These entities are an emerging class of highly potent biopharmaceutical drugs, best known in the field of oncology, that have been also designed as a targeted therapy/diagnosis for the treatment/prevention of several bacterial diseases. Antibiotic resistance is now a major threat to public health, and targeted strategies can reduce resistance. The following review aims at giving an overview of the patented therapeutic innovations covering these areas. Particular attention has been given to antibacterial drug conjugates in the last 30 years.
Areas covered The authors provide an overview of the scientific reports describing the research and development of new drug conjugates for bacterial diseases. The review emphasizes the rationale behind synthesis, biological activities and improvement of the new drug conjugates. New technologies applied for the research in this field have also been discussed. The article is based on the most relevant literature related to the development of new therapeutic solutions. The patents presented in this review have been collected from multiple electronic databases including SciFinder, Pubmed, Espacenet and Mendeley.
Expert opinion The new drug conjugates described in the current review proved to display improved delivery, efficacy, targeting abilities and fewer side effects. Versatile approaches were invented to achieve these goals.
... Mice were rendered neutropenic by injection with cyclophosphamide, and then MRSA was administered intramuscularly to one thigh. 29 Starting 1 h after infection, the compounds were dosed subcutaneously at 20 mg/kg three times a day (every 8 h) and the infected and uninfected thighs and plasma were harvested at 24 h. Linezolid (10 mg/kg) was used as a positive control and the vehicle as a negative control. ...
We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure-activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability, and shows efficacy in a mouse neutropenic thigh infection model.
... TD-1792 was evaluated in a phase II clinical study for the treatment of complicated skin and skin structure infections caused by Gram-positive bacteria, including resistant strains such as MRSA. Phase III clinical study was recently completed and clinical efficacy and safety were evaluated within an expanded patient population [40,41,42,43]. ...
Introduction:
Methicillin-resistant Staphylococcus aureus (MRSA) have been on the increase during the past decade, due to the steady growth of the elderly and immunocompromised patients, and the emergence of multidrug-resistant (MDR) bacterial strains. Although there are a limited number of anti-MRSA drugs available, a number of different combination antimicrobial drug regimens have been used to treat serious MRSA infections. Thus, the addition of several new antistaphylococcal drugs into clinical practice should broaden clinician's therapeutic options. As MRSA is one of the most common and problematic bacteria associated with increasing antimicrobial resistance, continuous efforts for the discovery of lead compounds as well as development of alternative therapies and faster diagnostics are required.
Areas covered:
This article summarizes the FDA-approved drugs to treat MRSA infections, the drugs in clinical trials, and the drug leads for MRSA and related Gram-positive bacterial infections. In addition, the article discusses the mode of action of antistaphylococcal molecules and the resistant mechanisms of some molecules.
Expert opinion:
The number of pipeline drugs presently undergoing clinical trials is not particularly encouraging. There are limited and rather expensive therapeutic options for MRSA infections in the critically ill. Further research efforts are required for effective phage therapy on MRSA infections in clinical use, which seem to be attractive therapeutic options for the future.
... LZD (0.4 mg/mouse; 12 mg/kg of body weight) or vancomycin (VCM) (Shionogi & Co., Ltd., Osaka, Japan) (1 mg/mouse; 40 mg/kg) was subcutaneously (s.c.) admin-istered to mice immediately after intranasal administration of MRSA suspension (30 l/mouse; approximately 10 6 to 10 7 CFU/mouse). The administration doses of LZD and VCM were determined by reference to the previous reports (1,2,12,13,30,31). In some experiments, lower doses of LZD than described in the previous reports were selected to evaluate antiinflammatory effects not related to the bacterial killing effects. ...
In the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistance Staphylococcus aureus (MRSA) infections were evaluated. We have retrospectively reviewed treatment effects of LZD on 52 patients with severe MRSA infections. Sixty-four percent of the febrile patients demonstrated significant defervescence within 3 days, despite the presence of positive culture results. We speculated that this finding might be due to early anti-inflammatory effects of LZD, and to investigate this further we initiated in vivo experiments using mice MRSA pneumonia models. Mice were treated with either LZD or vancomycin (VCM) immediately after intranasal administration of MRSA. Bacterial numbers and levels of inflammatory cytokines in the lungs were determined. Although the bacterial burden in the lungs was not apparently different between the two groups, LZD but not VCM treatment significantly reduced induction of inflammatory cytokines in the lungs (P < 0.05). To evaluate whether this anti-inflammatory response was due to suppression of virulence factor expression, filter-sterilized supernatants of MRSA incubated in broth overnight with sub-MICs of LZD were subcutaneously administered to mice. To clarify whether LZD possesses direct host-modulating activity, cytokine responses to the supernatants were examined in mice pretreated with LZD. Interestingly, MRSA solutions prepared in the presence of sub-MICs of LZD revealed significant suppression of interleukin 6 (IL-6) in a dose-dependent manner (P < 0.05), but pretreatment of mice with LZD revealed no changes in cytokines. These findings suggest that sub-MICs of LZD might suppress virulence factors of MRSA, which may be associated with a reduction in endogenous pyrogens. These data may explain at least in part early defervescence observed in LZD-treated individuals.
... isolates are inhibited (0.06 g/ml) for 24 h (15). At this dose, serum concentrations are predicted to exceed the AUC/MIC target ratio required for efficacy in vivo (7). This survey of the susceptibilities of multidrug-resistant S. aureus isolates to TD-1792, together with the favorable in vitro pharmacodynamic interactions described herein, supports the continued development of this new agent for the treatment of serious infections caused by S. aureus. ...
TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. The
in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S. aureus (MIC90, 0.015 μg/ml), methicillin-resistant S. aureus, and heterogeneous vancomycin-intermediate S. aureus (MIC90, 0.03 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of ≤0.12 μg/ml.
A postantibiotic effect of >2 h was observed after exposure to TD-1792.
The development of effective antibacterial solutions has become paramount in maintaining global health in this era of increasing bacterial threats and rampant antibiotic resistance. Traditional antibiotics have played a significant role in combating bacterial infections throughout history. However, the emergence of novel resistant strains necessitates constant innovation in antibacterial research. We have analyzed the data on antibacterials from the CAS Content Collection, the largest human-curated collection of published scientific knowledge, which has proven valuable for quantitative analysis of global scientific knowledge. Our analysis focuses on mining the CAS Content Collection data for recent publications (since 2012). This article aims to explore the intricate landscape of antibacterial research while reviewing the advancement from traditional antibiotics to novel and emerging antibacterial strategies. By delving into the resistance mechanisms, this paper highlights the need to find alternate strategies to address the growing concern.
Staphylococcus aureus is a leading cause of septicemia, endocarditis, pneumonia, skin and soft tissue infections, bone and joint infections, and hospital-acquired infections. In particular, methicillin-resistant Staphylococcus aureus (MRSA) is associated with high morbidity and mortality, and continues to be a major public health problem. The emergence of multidrug-resistant MRSA strains along with the wide consumption of antibiotics has made anti-MRSA treatment a huge challenge. Novel treatment strategies (e.g., novel antimicrobials and new administrations) against MRSA are urgently needed. In the past decade, pharmaceutical companies have invested more in the research and development (R&D) of new antimicrobials and strategies, spurred by favorable policies. All research articles were collected from authentic online databases, including Google Scholar, PubMed, Scopus, and Web of Science, by using different combinations of keywords, including ‘anti-MRSA’, ‘antibiotic’, ‘antimicrobial’, ‘clinical trial’, ‘clinical phase’, clinical studies’, and ‘pipeline’. The information extracted from articles was compared to information provided on the drug manufacturer’s website and Clinical- Trials.gov (https://clinicaltrials.gov/) to confirm the latest development phase of anti- MRSA agents. The present review focuses on the current development status of new anti-MRSA strategies concerning chemistry, pharmacological target(s), indications, route of administration, efficacy and safety, pharmacokinetics, and pharmacodynamics, and aims to discuss the challenges and opportunities in developing drugs for anti-MRSA infections.
