New Developments in Drug Treatment
Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies in Clinical Tuberculosis, 2020
Sutezolid is structurally highly similar to linezolid, differing only by a single sulfur atom, but has superior anti-TB activity.60 Its MIC is approximately 2−4-fold lower than linezolid for a range of clinical isolates,67 and in the mouse model it is bactericidal and more active than linezolid.60,68 Combined with first-line therapy it was able to accelerate the time to culture conversion in the lungs of mice, confirming that it has sterilizing activity.69 Combining sutezolid with bedaquiline, clofazimine, and pretomanid in a murine model resulted in a regimen that was highly active and achieved low relapse rates after only 3 months of therapy.15 There was no evidence of antagonism between these agents and this suggests an oxazolidinone could become a key part of a new universal regimen. Sutezolid has now demonstrated EBA over the course of 14 days in humans, a result that was not previously seen with linezolid and appears to confirm the improved antimycobacterial activity of sutezolid over linezolid. Rates of mitochondrial inhibition are likely to be lower with sutezolid and this is reflected in lower rates of clinical toxicity in limited duration human studies, however, these results need to be replicated over longer treatment periods.70,71 A phase IIb dose-finding study is now planned (NCT03959566).
Sutezolid
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Oxazolidinone antibiotics inhibit bacterial protein synthesis by binding in the peptidyl transferase active site of both bacterial and eukaryotic mitochondrial ribosomes, thereby preventing the proper placement of the tRNA and disrupting peptide bond formation and protein synthesis (Leach et al., 2007). This is consistent with the finding that oxazolidinones competitively inhibit chloramphenicol, known to bind in a similar location (Lin et al., 1997; Schlunzen et al., 2001). Mutations at this site have also been implicated in linezolid resistance in other organisms (Kloss et al., 1999; Meka et al., 2004; Prystowsky et al., 2001; Xiong et al., 2000; Wong et al., 2010; Farrell et al., 2009; Liakopoulos et al., 2009). Because the binding location is similar in eukaryotic mitochondrial ribosomes, the side effects of this drug class are likely also mediated through this mechanism (Leach et al., 2007).
New Developments in Drug Treatment
Peter D O Davies, Stephen B Gordon, Geraint Davies in Clinical Tuberculosis, 2014
Sutezolid is structurally highly similar to linezolid, differing only by a single sulphur atom, but it has superior anti-tuberculosis activity [47]. Its MIC is approximately two- to four-fold lower than linezolid for a range of clinical isolates [51], and in the mouse model, it is bactericidal and more active than linezolid [47,52]. Combined with first-line therapy, it was able to accelerate the time to culture conversion in the lungs of mice, confirming that it has sterilising activity [53]. Combining sutezolid with bedaquiline, clofazimine and PA-824 resulted in a regime that was highly active and achieved low relapse rates after only three months of therapy [13]. There was no evidence of antagonism between these agents, and this suggests an oxazolidinone could become a key part of a new universal regimen. Sutezolid is now under evaluation in an early bactericidal studies (EBA) study. Given its close similarity to linezolid, there are still concerns that it may have an overlapping toxicity profile, especially because it has not yet been used for longer treatment periods that exposed linezolid toxicity. However, with AZD5847 (which is structurally different from sutezolid) also entering phase II evaluation, there is a good chance that at least one oxazolidinone will have a clean safety profile to allow it to become a key component of a new regimen.
A cost minimisation analysis comparing oral linezolid and intravenous daptomycin administered via an outpatient parenteral antibiotic therapy programme in patients requiring prolonged antibiotic courses
Published in Journal of Chemotherapy, 2023
Linezolid is a synthetic antibiotic belonging to the oxazolidinone class. It acts by inhibiting initiation of protein synthesis at the 50S ribosome. It is active against a wide-range of gram-positive aerobic bacteria, some anaerobic bacteria, several mycobacterial species as well as nocardia [16]. First discovered in the mid-1990s, it was first approved for clinical use on April 18th 2000. When taken oral it has a bioavailability of nearly 100% and an extensive volume of distribution [17]. Its current licence allows it to be prescribed for a maximum of 28 days continuously after which the rates of adverse events increase. The main adverse effect leading to discontinuation when given for short courses is reversible myelosuppression [18]. With courses longer than 28 days, effects associated with mitochondrial toxicity such as peripheral neuropathy, hyperlactataemia and metabolic acidosis occur [19]. It has a clinically important drug interaction with serotonergic agents such as the commonly prescribed class of antidepressants selective serotonin reuptake inhibitors (SSRIs) which limits use in these patients [20]. It is not licensed for use in catheter-related BSI (CR-BSI) due to a small imbalance in mortality in an early open-label study of the drug [21]. Patent protection expired in 2015 leading to entry to the market of generic competitors and considerable reduction in price of linezolid.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
Similarly, oxazolidinone-based antibiotics are known to bind to the peptidyltransferase center (PTC) of the 50S ribosomal subunit, preventing the formation of the initiation complex itself, thus resulting in inhibition of protein synthesis [36]. Oxazolidinone-based antibiotics are characterized by a core structure consisting of an oxazolidone ring with the S configuration of the substituent at C5, linked to an acylaminomethyl group and an N-aryl substituent [37]. The 50S ribosomal subunit is composed of 5S rRNA, the 23S rRNA, and structural proteins. Despite binding to rRNA in the ribosomal complex, the mechanism of action of oxazolidinone-based antibiotics differs greatly from aminoglycoside-based antibiotics and does not affect peptidyl elongation nor translational termination. Oxazolidinone-based antibiotics crosslink the 23S rRNA with other structural ribosomal proteins, binding to the universally conserved U2585 rRNA nucleotide, thereby stabilizing the base in an orientation that induces a nonproductive conformation of the PTC. Importantly, other RNA structures have been shown to efficiently bind to oxazolidinone derivatives and analogs. For instance, oxazolidinone analogs have been shown to bind to the non-ribosomal RNA T-box antiterminator, a key component of the T-box riboswitch [38] responsible for regulating RNA transcription in response to metabolic effector molecules in Gram-positive bacteria.
Optimization of dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus in neutropenic patients with cancer by Monte Carlo simulations
Published in Journal of Chemotherapy, 2021
Xiaochen Wei, Mingfeng Zhao, Xia Xiao
Linezolid, the first oxazolidinone, is an important therapeutic option for infections caused by resistant Gram-positive bacterial pathogens. Currently, there is controversy regarding the use of linezolid in patients with neutropenic because it is a bacteriostatic agent.23 Our simulation results suggested that the standard linezolid dosage (1200 mg/day) was appropriate against S.aureus with an MIC of 1 µg/mL at the AUC0-24/MIC index of ≥ 80 in neutropenic patients with cancer, and as the AUC0-24/MIC index increased from 80 to 120, the corresponding PTA decreased from 91.00% to 73.28%. For an MIC of 2 µg/mL, none of the simulated dosing regimens of linezolid could achieve a PTA value of ≥ 90% against S.aureus. Furthermore, CFRs of several linezolid simulated dosing regimens reached < 80% against MRSA at the AUC0-24/MIC values of 80-120, indicating a lower success probability for infection in neutropenic patients with cancer. These results were similar to a previous PK/PD study report that linezolid dosing regimens (600 mg q8h or 600 mg q6h) applied to MRSA did not achieve CFRs > 80% in critically ill patients, and so an in-depth optimisation strategy for the dosing regimen needs to be considered for patients infected by MRSA. In addition, one should acknowledge that reports of myelosuppression could be a potential limitation for the use of linezolid in neutropenic patients with cancer.23
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