RESUMEN
Rifamycin antibiotics such as rifampin are potent inhibitors of prokaryotic RNA polymerase (RNAP) used to treat tuberculosis and other bacterial infections. Although resistance arises in the clinic principally through mutations in RNAP, many bacteria possess highly specific enzyme-mediated resistance mechanisms that modify and inactivate rifamycins. The expression of these enzymes is controlled by a 19-bp cis-acting rifamycin-associated element (RAE). Guided by the presence of RAE sequences, we identify a helicase-like protein, HelR, in Streptomyces venezuelae that confers broad-spectrum rifamycin resistance. We show that HelR also promotes tolerance to rifamycins, enabling bacterial evasion of the toxic properties of these antibiotics. HelR forms a complex with RNAP and rescues transcription inhibition by displacing rifamycins from RNAP, thereby providing resistance by target protection . Furthermore, HelRs are broadly distributed in Actinobacteria, including several opportunistic Mycobacterial pathogens, offering yet another challenge for developing new rifamycin antibiotics.
Asunto(s)
Rifamicinas , Tuberculosis , Antibacterianos/farmacología , ARN Polimerasas Dirigidas por ADN/genética , ARN Polimerasas Dirigidas por ADN/metabolismo , Humanos , Rifampin/metabolismo , Rifampin/farmacología , Rifamicinas/farmacología , Streptomyces/enzimologíaRESUMEN
Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered-compared with rifampicin-conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance.
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Productos Biológicos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Rifabutina/farmacología , Rifampin/farmacología , Rifamicinas/farmacología , Antituberculosos/farmacología , ARN Polimerasas Dirigidas por ADN/genética , Farmacorresistencia Bacteriana/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Mutación/efectos de los fármacos , Mutación/genética , Mycobacterium tuberculosis/genética , Thermus thermophilus/efectos de los fármacos , Thermus thermophilus/genéticaRESUMEN
BACKGROUND: Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR). METHODS: To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment. RESULTS: Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01-10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment. CONCLUSION: The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022327337.
Asunto(s)
Antituberculosos , Infecciones por VIH , Rifamicinas , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Rifamicinas/uso terapéutico , Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Factores de Riesgo , Mycobacterium tuberculosis/efectos de los fármacos , Sudáfrica/epidemiologíaRESUMEN
BACKGROUND: Real-world experience with combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor (InSTI)-containing antiretroviral therapy (ART) in management of latent tuberculous infection (LTBI) is limited among people with HIV (PWH). METHODS: From August 2019 to October 2022, PWH receiving 3 months of weekly rifapentine plus isoniazid (3HP) or 1 month of daily rifapentine plus isoniazid (1HP) in combination with ART were included. The primary outcome was virologic response within 12 months after LTBI treatment, and the secondary outcomes included treatment completion rate and safety of LTBI regimens. RESULTS: During the study period, 479 PWH (94.6% male; median age, 43 years) were included: 142 received 1HP and bictegravir (BIC)-containing regimens (1HP/BIC group), 46 1HP and dolutegravir (DTG)-containing regimens (1HP/DTG group), 38 3HP and BIC-containing regimens (3HP/BIC group), 214 3HP and DTG-containing regimens (3HP/DTG group), 17 1HP and other ART regimens (1HP/others group), and 22 3HP/other ART regimens (3HP/others group). In the intention-to-treat analysis, the proportions of PWH maintaining plasma HIV-1 RNA <200â copies/mL within 12 months after LTBI treatment completion were 96.5% (1HP/BIC), 100% (1HP/DTG), 100% (3HP/BIC), 95.8% (3HP/DTG), 100% (1HP/others), and 100% (3HP/others). The overall completion rates were >80% for all treatment groups, whereas >50% of the included PWH experienced any adverse event. LTBI regimens and ART combinations were not associated with virologic response and completion rate. CONCLUSION: Combinations of short-course rifapentine-based regimens and InSTI-containing ART maintained viral suppression for most PWH within 12 months of LTBI treatment completion with low rates of grade 3 or higher adverse events.
RESUMEN
Eight rifamycin-related polyketides were isolated from the culture broth of a marine-derived bacterium Salinispora arenicola, including five known (2-5 and 8) and three new derivatives (1, 6, and 7). The structures of the new compounds were determined by means of spectroscopic methods (HRESIMS and 1D, 2D NMR) and a comparison of their experimental data with those previously reported in the literature. The isolated compounds were evaluated for their cytotoxicity against one normal, six solid, and seven blood cancer cell lines and 1 showed moderate activity against all the tested cell lines with GI50 values ranging from 2.36 to 9.96 µM.
RESUMEN
This review summarizes the literature data reported from 2000 up to the present on the development of various electrochemical (voltammetric, amperometric, potentiometric and photoelectrochemical), optical (UV-Vis and IR) and luminescence (chemiluminescence and fluorescence) methods and the corresponding sensors for rifamycin antibiotics analysis. The discussion is focused mainly on the foremost compound of this class of macrocyclic drugs, namely rifampicin (RIF), which is a first-line antituberculosis agent derived from rifampicin SV (RSV). RIF and RSV also have excellent therapeutic action in the treatment of other bacterial infectious diseases. Due to the side-effects (e.g., prevalence of drug-resistant bacteria, hepatotoxicity) of long-term RIF intake, drug monitoring in patients is of real importance in establishing the optimum RIF dose, and therefore, reliable, rapid and simple methods of analysis are required. Based on the studies published on this topic in the last two decades, the sensing principles, some examples of sensors preparation procedures, as well as the performance characteristics (linear range, limits of detection and quantification) of analytical methods for RIF determination, are compared and correlated, critically emphasizing their benefits and limitations. Examples of spectrometric and electrochemical investigations of RIF interaction with biologically important molecules are also presented.
Asunto(s)
Mycobacterium tuberculosis , Rifamicinas , Humanos , Rifampin/farmacología , Rifampin/uso terapéutico , Rifamicinas/farmacología , AntituberculososRESUMEN
Bacterial resistance threatens the utility of currently available antibiotics. Rifampicin, a cornerstone in the treatment of persistent Gram-positive infections, is prone to the development of resistance resulting from single point mutations in the antibiotic's target, RNA polymerase. One strategy to circumvent resistance is the use of 'hybrid' antibiotics consisting of two covalently linked antibiotic entities. These compounds generally have two distinct cellular targets, reducing the probability of resistance development and potentially providing simplified pharmacological properties compared to combination therapies using the individual antibiotics. Here we evaluate a series of semi-synthetic hybrid antibiotics formed by linking kanglemycin A (Kang A), a rifampicin analog, and a collection of fluoroquinolones. Kang A is a natural product antibiotic which contains a novel dimethyl succinic acid moiety that offers a new attachment point for the synthesis of hybrid antibiotics. We compare the activity of the Kang A hybrids generated via the acid attachment point to a series of hybrids linked at the compound's naphthoquinone ring system. Several hybrids exhibit activity against bacteria resistant to Kang A via the action of the partnered antibiotic, suggesting that the Kang scaffold may provide new avenues for generating antibiotics effective against drug-resistant infections.
Asunto(s)
Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Rifamicinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Farmacorresistencia Bacteriana/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Fluoroquinolonas/síntesis química , Fluoroquinolonas/toxicidad , Células HEK293 , Humanos , Pruebas de Sensibilidad Microbiana , Rifamicinas/síntesis química , Rifamicinas/toxicidad , Staphylococcus aureus/efectos de los fármacosRESUMEN
Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structure-based approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.
Asunto(s)
Mycobacterium , Rifamicinas , Antibacterianos/farmacología , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Rifamicinas/farmacología , Rifamicinas/química , ADP-RibosilaciónRESUMEN
Staphylococcus epidermidis is a major cause of periprosthetic joint infection (PJI); its intracellular persistence within osteoblasts may compromise therapy if that therapy is not intracellularly active. The intracellular activity of rifampin, rifapentine, and rifabutin was assessed against five rifampin-susceptible and two rifampin-resistant S. epidermidis isolates. Compared to no treatment, treatment resulted in a ≥2-fold log10 reduction of intracellular rifampin-susceptible, but not rifampin-resistant, S. epidermidis These findings show activity of rifampin, rifapentine, and rifabutin against intraosteoblast PJI-associated S. epidermidis.
Asunto(s)
Infecciones Relacionadas con Prótesis , Rifampin , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Humanos , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Rifabutina/farmacología , Rifampin/análogos & derivados , Rifampin/farmacología , Staphylococcus epidermidisRESUMEN
Rifamycins, such as rifampicin (Rif), are potent inhibitors of bacterial RNA polymerase (RNAP) and are widely used antibiotics. Rifamycin resistance is usually associated with mutations in RNAP that preclude rifamycin binding. However, some bacteria have a type of ADP-ribosyl transferases, Arr, which ADP-ribosylate rifamycin molecules, thus inactivating their antimicrobial activity. Here, we directly show that ADP-ribosylation abolishes inhibition of transcription by rifampicin, the most widely used rifamycin antibiotic. We also show that a natural rifamycin, kanglemycin A (KglA), which has a unique sugar moiety at the ansa chain close to the Arr modification site, does not bind to Arr from Mycobacterium smegmatis and thus is not susceptible to inactivation. We, found, however, that kanglemycin A can still be ADP-ribosylated by the Arr of an emerging pathogen, Mycobacterium abscessus. Interestingly, the only part of Arr that exhibits no homology between the species is the part that sterically clashes with the sugar moiety of kanglemycin A in M. smegmatis Arr. This suggests that M. abscessus has encountered KglA or rifamycin with a similar sugar modification in the course of evolution. The results show that KglA could be an effective antimicrobial against some of the Arr-encoding bacteria.
Asunto(s)
Rifamicinas , ADP-Ribosilación , Pruebas de Sensibilidad Microbiana , Rifampin/farmacología , Rifamicinas/farmacologíaRESUMEN
Mycobacterium abscessus exhibits Arr (ADP-ribosyltransferase)-dependent rifampin resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in M. abscessus infection models, implying that RBT might not be inactivated by Arr. RBT susceptibility testing of M. abscessusΔarr revealed a strongly decreased MIC. Our findings suggest that the efficacy of RBT might be enhanced by rendering RBT resilient to Arr-dependent modification or by blocking M. abscessus Arr activity.
Asunto(s)
Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , ADP Ribosa Transferasas , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium abscessus/genética , Rifabutina/farmacología , Rifampin/farmacologíaRESUMEN
Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat Mycobacterium abscessus infections due to poor in vitro activity. While rifabutin, another rifamycin, has better anti-M. abscessus activity, its activity is far from the nanomolar potencies of rifamycins against Mycobacterium tuberculosis. Here, we asked (i) why is rifabutin more active against M. abscessus than rifampicin, and (ii) why is rifabutin's anti-M. abscessus activity poorer than its anti-TB activity? Comparative analysis of naphthoquinone- versus naphthohydroquinone-containing rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase ArrMab like rifampicin, preventing it from achieving the nanomolar activity that it displays against M. tuberculosis. Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that rifamycins more potent than rifabutin should contain the molecule's naphthoquinone core plus a modification that blocks ADP-ribosylation at its C-23. To test these predictions, we performed a blinded screen of a diverse collection of 189 rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively resistant naphthoquinone core and C-25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to rifamycins and provides proof of concept for the repositioning of rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.
Asunto(s)
Mycobacterium abscessus , Rifamicinas , ADP-Ribosilación , Pruebas de Sensibilidad Microbiana , Rifabutina/farmacología , Rifamicinas/farmacologíaRESUMEN
Cutaneous leishmaniasis is challenging to treat. Various drugs have been proposed to manage this condition, with variable results. In this case report, we describe laser-assisted delivery of rifamycin to treat this infection. Two sessions of fractional CO2 laser were performed one month apart. Each was followed by a topical application of rifamycin for three days. Resolution with minimal scarring was obtained, suggesting this technique might be safe and effective in treating cutaneous leishmaniasis.
Asunto(s)
Láseres de Gas , Leishmaniasis Cutánea , Preparaciones Farmacéuticas , Rifamicinas , Administración Cutánea , Dióxido de Carbono , Niño , Humanos , Leishmaniasis Cutánea/tratamiento farmacológicoRESUMEN
BACKGROUND: Owing to patient intolerance or drug interactions, alternative agents to rifampin are needed for management of staphylococcal periprosthetic joint infection. In the current study, we evaluated rifabutin, rifapentine and rifampin, with and without vancomycin, in a rat model of foreign body osteomyelitis. METHODS: Proximal tibiae were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and a Kirschner wire (K-wire) implanted in each. After 4 weeks of infection, rifampin, rifabutin, or rifapentine were administered, alone or with vancomycin. Tibiae and K-wires were cultured, and medians were reported as log10 colony-forming units (CFUs) per gram of bone or log10 CFUs per K-wire, respectively. RESULTS: Rifampin, rifabutin or rifapentine administered with vancomycin yielded less MRSA from bones (0.10, 3.02, and 0.10 log10 CFUs/g, respectively) than did no treatment (4.36 log10 CFUs/g) or vancomycin alone (4.64 log10 CFUs/g) (both Pâ ≤â .02). The K-wires of animals receiving no treatment or vancomycin monotherapy recovered medians of 1.76 and 2.91 log10 CFUs/g per K-wire, respectively. In contrast, rifampin, rifabutin and rifapentine administered with vancomycin yielded medians of 0.1 log10 CFUs per K-wire, respectively. Rifampin resistance was detected in a single animal in the rifampin monotherapy group. CONCLUSIONS: Rifabutin or rifapentine with vancomycin were as active as rifampin with vancomycin against MRSA in rat foreign body osteomyelitis, suggesting that rifabutin and/or rifapentine may be alternatives to rifampin in the clinical management of staphylococcal periprosthetic joint infections.
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Antibacterianos/uso terapéutico , Cuerpos Extraños/microbiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Osteomielitis/microbiología , Rifabutina/uso terapéutico , Rifampin/análogos & derivados , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Cuerpos Extraños/complicaciones , Masculino , Osteomielitis/etiología , Ratas , Ratas Wistar , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Infecciones Estafilocócicas/etiología , Vancomicina/administración & dosificación , Vancomicina/uso terapéuticoRESUMEN
Chronic otitis media is one of the most common ear pathologies among children. This article provides a short overview of publications on surgical techniques. Currently, the most effective treatment is the surgical sanitation of the middle ear cavities. There are two fundamentally different approaches of operations in relation to the posterior wall of the external auditory canal - «open¼ and «closed¼ types. Both methods have their advantages and disadvantages, which are especially noticeable in pediatric revision otosurgery. Surgical obliteration of the sanitized middle ear cavities is an effective compromise option. However, the techniques of bone obliteration, which are actively applied among adults, are difficult if we discuss children ear. A way out of this situation may be the use of modern osteoplastic materials for filling large trepanation cavities. The article describes in detail the technique of revision sanitizing surgery on the middle ear using osteoplastic granules. Purpose of the study. The analysis of the first results of separate obliteration of paratympanic cavities in children using osteoplastic materials. MATERIAL AND METHODS: In the period from May 2018 to November 2020, on the basis of the Federal State Autonomous Institution «National Medical Research Center of Children's Health¼ of the Ministry of Health of Russia, 28 children aged from 6 to 17-year-old with chronic otitis media and cholesteatoma were operated using osteoplastic obliteration, who had previously sanitizing operation on the middle ear. All children on admission to the hospital and 6-12 months after the operation underwent a complex examination. The condition of each patient was assessed using the OMO-22 quality of life questionnaire, to which the parents answered the questions twice - before and 1 year after surgery. RESULTS: During the postoperative period none of the patients had clinical signs of recurrence of cholesteatoma, which was confirmed by CT scan. When assessing the quality of life of children using a questionnaire, the average score before the operation was 130.2±27.7, after the operation - 61.5±21.1. The indicator of the bone-air interval before surgery in patients averaged 29.8±9.7 dB, 1 year after surgery - 13.0±10.9 dB (p>0.05). FINDINGS: The first experience of using osteoplastic materials for obliterating the paratympanic spaces in children has shown high efficiency, ease of use and safety.
Asunto(s)
Colesteatoma del Oído Medio , Calidad de Vida , Adolescente , Adulto , Anciano , Niño , Colesteatoma del Oído Medio/cirugía , Conducto Auditivo Externo , Oído Medio/diagnóstico por imagen , Oído Medio/cirugía , Humanos , Apófisis Mastoides , Estudios Retrospectivos , Federación de Rusia , TimpanoplastiaRESUMEN
There is no reliable cure for Mycobacterium abscessus lung disease. Rifampin is not used clinically due to poor in vitro potency. In contrast, we have shown that rifabutin, another approved rifamycin used to treat tuberculosis, is potent in vitro against M. abscessus Here, we report that rifabutin is as active as clarithromycin against M. abscessus K21 in NOD.CB17-Prkdcscid/NCrCrl mice. This suggests that rifabutin should be considered a repurposing candidate for patients with M. abscessus disease.
Asunto(s)
Antibacterianos/farmacología , Enfermedades Pulmonares/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium abscessus/efectos de los fármacos , Rifabutina/farmacología , Animales , Antibacterianos/química , Claritromicina/farmacología , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Femenino , Humanos , Enfermedades Pulmonares/microbiología , Ratones , Ratones Endogámicos NOD , Infecciones por Mycobacterium no Tuberculosas/microbiología , Rifabutina/químicaRESUMEN
Mycobacterium abscessus is the most difficult-to-treat nontuberculous mycobacteria because of its resistance to many antibiotics. In this study, we screened the Korea Chemical Bank library for a bioluminescent reporter assay to identify molecules capable of acting against M. abscessus. On application of the assay, rifamycin O showed excellent in vitro activity with a narrow range of the minimum inhibitory concentration required to inhibit the growth of 90% of the bacterium (MIC90 = 4.0-6.2 µM); its in vivo efficacy in the zebrafish (Danio rerio) infection model was comparable to that of rifabutin at 25 µM. Furthermore, rifamycin O did not show significant toxicity in cells and the zebrafish model. These results are the first in vivo indication that rifamycin O may be a drug candidate for treating M. abscessus infections.
Asunto(s)
Antibacterianos/farmacología , Mycobacterium abscessus/efectos de los fármacos , Rifamicinas/farmacología , Animales , Antibacterianos/química , Humanos , Mediciones Luminiscentes , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Rifamicinas/química , Pez CebraRESUMEN
Amycolatopsis mediterranei S699 produces rifamycin B and successors of this strain are in use for the industrial production of rifamycin B. Semisynthetic derivatives of rifamycin B are used against Mycobacterium tuberculosis that causes tuberculosis. Although the rifamycin biosynthetic gene cluster was characterized two decades ago, the regulation of rifamycin B biosynthesis in Amycolatopsis mediterranei S699 is poorly understood. In this study, we analysed the genome and proteome of Amycolatopsis mediterranei S699 and identified 1102 transcription factors which comprise about 10% of the total genome. Using interactomics approaches we delineated 30 unique transcription factors directly involved in secondary metabolism that regulate rifamycin B biosynthesis. We also predict the role of RifN as hub in controlling the regulation of other genes involved in rifamycin biosynthesis. RifN is important for maintaining the integrity of the rifamycin-network. Thus, these transcription factor can be exploited to improve rifamycin B production in Amycolatopsis mediterranei S699.
RESUMEN
THE PURPOSE OF THE WORK: Is to study the efficacy of treatment of exacerbation of chronic tubotympanic purulent otitis media with Otofa drug with the active substance Rifamycin. MATERIAL AND METHODS: Performed a retrospective analysis of 37 medical histories of patients who applied to the otorhinolaryngology clinic with a diagnosis of exacerbation of chronic purulent tubotympanic otitis media in the period from January 2019 to December 2019. RESULTS: Noted relief of symptoms such as throbbing noise and pain in patients receiving the topical Otofa drug (active ingredient Rifamycin) by the 3th day of therapy. Otofa also reduced otorrhea by the 5th day of therapy. CONCLUSION: The study showed the high clinical efficacy of Otofa ear drops containing the Rifamycin antibiotic.
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Otitis Media Supurativa , Otitis Media , Antibacterianos , Enfermedad Crónica , Tratamiento Conservador , Humanos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Staphylococcus aureus causes serious bacterial infections with high morbidity and mortality, necessitating the discovery of new antibiotics. DSTA4637S is a novel antibody-antibiotic conjugate designed to target intracellular S. aureus that is not adequately eliminated by current standard-of-care antibiotics. DSTA4637S is composed of an anti-S. aureus Thiomab human immunoglobulin G1 (IgG1) monoclonal antibody linked to a novel rifamycin-class antibiotic (4-dimethylaminopiperidino-hydroxybenzoxazino rifamycin [dmDNA31]) via a protease-cleavable linker. Phagocytic cells ingest DSTA4637S-bound S. aureus, and intracellular cathepsins cleave the linker, releasing dmDNA31and killing intracellular S. aureus This first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose phase 1 trial analyzed the safety, pharmacokinetics, and immunogenicity of DSTA4637S in healthy volunteers. Thirty healthy male and female volunteers, 18-65 years old, were randomized into five cohorts receiving single intravenous (i.v.) doses of 5, 15, 50, 100, and 150 mg/kg of DSTA4637S or placebo (4 active:2 placebo). Subjects were followed for 85 days after dosing. No subject withdrew from the study, and no serious or severe adverse events occurred. One moderate infusion-related reaction (150 mg/kg DSTA4637S) occurred. No clinically meaningful or dose-related changes in laboratory parameters or vital signs occurred. Pharmacokinetics of plasma DSTA4637S conjugate and serum DSTA4637S total antibody were dose proportional. Systemic exposure of unconjugated dmDNA31 was low. No DSTA4637S-induced anti-drug antibody responses were observed. DSTA4637S was generally safe and well tolerated as a single i.v. dose in healthy volunteers. DSTA4637S has a favorable safety and pharmacokinetic profile that supports future development as a novel therapeutic for S. aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02596399.).