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INTRODUCTION: Many of the first line medications for the treatment of active and latent M. tuberculosis are hepatoxic and cause a spectrum of anti-tuberculosis drug induced liver injury (ATLI), including acute liver failure (ALF). Despite advances in recognition of and prevention of ATLI, isoniazid remains one of the leading causes of DILI as well as drug-induced ALF. AREAS COVERED: A literature search of the incidence, risk factors, current societal guidelines, monitoring, and prophylactic medication usage in ATLI was performed using PubMed and institutional websites. Relevant articles from 1972 to 2024 were included in this review. EXPERT OPINION: Current societal guidelines regarding ATLI monitoring are mixed, but many recommend liver enzyme testing of high-risk populations. We recommend liver test monitoring for all patients on multi-drug therapy as well as those on isoniazid therapy. Precision medicine practices, such as N-acetyltransferase-2 polymorphism genotyping, are thought to be beneficial in reducing the incidence of ATLI in high-risk populations. However, broader implementation is currently cost prohibitive. Hepatoprotective drugs are not currently recommended, although we do recognize their potential. In patients who develop ATLI but require ongoing anti-TB treatment, strategies to restart the same or less hepatotoxic regimens are currently being followed.

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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.

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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 <200 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.

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BACKGROUND: The coexistence of lung cancer and tuberculosis is not rare. Rifamycin plays a pivotal role in anti-tuberculosis therapy. However, its potential impact on the liver metabolism of oncology drugs raises concerns. We performed this study to explore whether Rifamycin affects the survival of patients with tuberculosis and lung cancer. METHODS: Drawing from the Taiwan National Health Insurance Research Database, we identified patients diagnosed with concurrent lung cancer and tuberculosis between 2000 and 2014. Patients were categorized based on whether they underwent rifamycin-inclusive or rifamycin-exempt anti-tuberculosis therapy. Subsequently, we paired them at a 1:1 ratio and evaluated the mortality risk over a two-year span. RESULTS: Out of the study participants, 1558 (81.4%) received rifamycin-based anti-tuberculosis therapy, while 356 (18.6%) underwent a rifamycin-free regimen. Analysis revealed no marked variance in the biennial mortality rate between the groups (adjusted hazard ratio: 1.33, 95% confidence interval 0.93-1.90, p = 0.1238). When focusing on the matched sets comprising 127 individuals in each group, the data did not indicate a significant link between rifamycin and a heightened two-year mortality risk (adjusted hazard ratio: 1.00, 95% confidence interval 0.86-1.18, p = 0.9538). CONCLUSIONS: For individuals with concomitant lung cancer and tuberculosis, rifamycin's administration did not adversely influence two-year survival. Thus, rifamycin-containing anti-TB regimens should be prescribed for the indicated patients.

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The success of the TB control program is hampered by the major issue of drug-resistant tuberculosis (DR-TB). The situation has undoubtedly been made more difficult by the widespread and multidrug-resistant (XDR) strains of TB. The modification of existing anti-TB medications to produce derivatives that can function on resistant TB bacilli is one of the potential techniques to overcome drug resistance affordably and straightforwardly. In comparison to novel pharmaceuticals for drug research and progress, these may have a better half-life and greater bioavailability, be more efficient, and serve as inexpensive alternatives. Mycobacterium tuberculosis, which is drugsusceptible or drug-resistant, is effectively treated by several already prescribed medications and their derivatives. Due to this, the current review attempts to give a brief overview of the rifampicin derivatives that can overcome the parent drug's resistance and could, hence, act as useful substitutes. It has been found that one-third of the global population is affected by M. tuberculosis. The most common cause of infection-related death can range from latent TB to TB illness. Antibiotics in the rifamycin class, including rifampicin or rifampin (RIF), rifapentine (RPT), and others, have a special sterilizing effect on M. tuberculosis. We examine research focused on evaluating the safety, effectiveness, pharmacokinetics, pharmacodynamics, risk of medication interactions, and other characteristics of RIF analogs. Drug interactions are especially difficult with RIF because it must be taken every day for four months to treat latent TB infection. RIF continues to be the gold standard of treatment for drug-sensitive TB illness. RIF's safety profile is well known, and the two medicines' adverse reactions have varying degrees of frequency. The authorized once-weekly RPT regimen is insufficient, but greater dosages of either medication may reduce the amount of time needed to treat TB effectively.

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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.

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Antimicrobial resistance has emerged as a global public health threat, and development of novel therapeutics for treating infections caused by multi-drug resistant bacteria is urgent. Staphylococcus aureus is a major human and animal pathogen, responsible for high levels of morbidity and mortality worldwide. The intracellular survival of S. aureus in macrophages contributes to immune evasion, dissemination, and resilience to antibiotic treatment. Here, we present a confocal fluorescence imaging assay for monitoring macrophage infection by green fluorescent protein (GFP)-tagged S. aureus as a front-line tool to identify antibiotic leads. The assay was employed in combination with nanoscaled chemical analyses to facilitate the discovery of a new, active rifamycin analogue. Our findings indicate a promising new approach for the identification of antimicrobial compounds with macrophage intracellular activity. The antibiotic identified here may represent a useful addition to our armory in tackling the silent pandemic of antimicrobial resistance.

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PURPOSE: This study aimed to evaluate the efficacy of a single-dose topical rifamycin application on postoperative complications after impacted lower third molar surgery. MATERIALS AND METHODS: This prospective, controlled clinical study consisted of individuals with bilaterally impacted lower third molars that would be extracted for orthodontic reasons. The extraction sockets were irrigated with 3 ml/250 mg of rifamycin solution in Group 1, while in Group 2 (control group) the extraction sockets were irrigated with 20 ml of physiological saline. Pain intensity was measured daily for 7 days by using visual analog scale. Trismus and edema were evaluated preoperatively and on the postoperative days 2 and 7 by calculating the proportional changes in maximum mouth opening and mean distance between reference points of the face, respectively. Paired samples t-test, Wilcoxon signed rank test and Chi-square test were used to analyze the study variables. RESULTS: 35 patients (19 female, 16 male) were included in the study. The mean age of all participants was 22.19±4.98. Alveolitis was observed in 8 patients, (6 in the control group, 2 in the rifamycin group). There was no statistically significant difference between groups in terms of trismus and swelling measurements on the 2nd and 7th postoperative days (p>0.05). VAS scores were significantly low in rifamycin group on postoperative days 1 and 4 (p<0.05). CONCLUSION: Within the limits of the present study, topical rifamycin application reduced the incidence of alveolitis, prevented infection, and provided analgesic effect after surgical removal of impacted third molars.

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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.

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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.

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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.

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Background: Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics. Method: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction. Results: The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients. Conclusion: The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

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Tuberculosis (TB) is a common infectious disease that is present all around the world. This insidious disease needs drastic measures for its eradication. One of the actions contributing to it is the timely diagnosis and offering suitable treatment options for latent tuberculosis patients. In this review, we will discuss and compare the variety of options available for this purpose. We searched PubMed/Medline, Cochrane library, Google Scholar, and Science Direct to find articles regarding the effectiveness, safety, and completion of any of the five regimens available for latent tuberculosis infection. These options are the most classic and standard nine months of isoniazid given daily, which is now more commonly given as six months course, three months of daily isoniazid and rifampin, three months of weekly isoniazid and rifapentine, and four months of daily rifampin. We looked into free full-text studies published from 2011 to 2021 available in English language and human studies. After applying inclusion/exclusion criteria and removing duplicates and screening, 34 articles were shortlisted for quality assessment check, after which we finalized nine studies. Cochrane risk-of-bias assessment tool was used for quality check of randomized control trials, New-Castle Ottawa tool for observational studies, and assessment of multiple systematic reviews (AMSTAR) tool for systematic reviews. Efficacy was checked by tracking down the new cases of TB in the sample population that took the treatment for latent tuberculosis infection. New rifamycin-based regimens were almost equal in effectiveness to isoniazid regimens. The side effect profile is different for both regimens, but short-duration courses tend to have a higher chance of completion.

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Tuberculosis (TB) is one of the most significant world health problems, responsible for 1.5 M deaths in 2020, and yet, current treatments rely largely on 40 year old paradigms. Although the rifamycins (RIFs), best exemplified by the drug rifampin (RMP), represent a well-studied and therapeutically effective chemotype that targets the bacterial RNA polymerase (RNAP), these agents still suffer from serious drawbacks including the following: 3-9 month treatment times; cytochrome P450 (Cyp450) induction [particularly problematic for human immunodeficiency virus-Mycobacterium tuberculosis (MTB) co-infection]; and the existence of RIF-resistant (RIFR) MTB strains. We have utilized a structure-based drug design approach to synthesize and test 15 benzoxazinorifamycins (bxRIFs), congeners of the clinical candidate rifalazil, to minimize human pregnane X receptor (hPXR) activation while improving potency against MTB. We have determined the compounds' activation of the hPXR [responsible for inducing Cyp450 3A4 (CYP3A4)]. Compound IC50s have been determined against the wild-type and the most prevalent RIFR (ß-S450L) mutant MTB RNAPs. We have also determined their bactericidal activity against "normal" replicating MTB and a model for non-replicating, persister MTB. We have identified a minimal substitution and have probed larger substitutions that exhibit negligible hPXR activation (1.2-fold over the dimethyl sulfoxide control), many of which are 5- to 10-fold more potent against RNAPs and MTB than RMP. Importantly, we have analogues that are essentially equipotent against replicating MTB and non-replicating persister MTB, a property that is correlated with faster kill rates and may lead to shorter treatment durations. This work provides a proof of principle that the ansamycin core remains an attractive and effective scaffold for novel and dramatically improved RIFs.

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Rifampin (RMP), a very potent inhibitor of the Mycobacterium tuberculosis (MTB) RNA polymerase (RNAP), remains a keystone in the treatment of tuberculosis since its introduction in 1965. However, rifamycins suffer from serious drawbacks, including 3- to 9-month treatment times, Cyp450 induction (particularly problematic for HIV-MTB coinfection), and resistant mutations within RNAP that yield RIF-resistant (RIFR) MTB strains. There is a clear and pressing need for improved TB therapies. We have utilized a structure-based drug design approach to synthesize and test novel benzoxazinorifamycins (bxRIF), congeners of the clinical candidate rifalazil. Our goal is to gain binding interactions that will compensate for the loss of RIF-binding affinity to the (RIFR) MTB RNAP and couple those with substitutions that we have previously found that essentially eliminate Cyp450 induction. Herein, we report a systematic exploration of 42 substituted bxRIFs that have yielded an analogue (27a) that has an excellent in vitro activity (MTB RNAP inhibition, MIC, MBC), enhanced (∼30-fold > RMP) activity against RIFR MTB RNAP, negligible hPXR activation, good mouse pharmacokinetics, and excellent activity with no observable adverse effects in an acute mouse TB model. In a time-kill study, 27a has a 7 day MBC that is ∼10-fold more potent than RMP. These results suggest that 27a may exhibit a faster kill rate than RMP, which could possibly reduce the clinical treatment time. Our synthetic protocol enabled the synthesis of ∼2 g of 27a at >95% purity in 3 months, demonstrating the feasibility of scale-up synthesis of bxRIFs for preclinical and clinical studies.

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[This corrects the article DOI: 10.3389/fcimb.2022.807610.].

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Rhodococcus equi is a zoonotic pathogen that can cause fatal disease in patients who are immunocompromised. At present, the epidemiology and pathogenic mechanisms of R. equi infection are not clear. This study characterized the genomes of 53 R. equi strains from different sources. Pan-genome analysis showed that all R. equi strains contained 11481 pan genes, including 3690 core genes and 602 ~ 1079 accessory genes. Functional annotation of pan genome focused on the genes related to basic lifestyle, such as the storage and expression of metabolic and genetic information. Phylogenetic analysis based on pan-genome showed that the R. equi strains were clustered into six clades, which was not directly related to the isolation location and host source. Also, a total of 84 virulence genes were predicted in 53 R. equi strains. These virulence factors can be divided into 20 categories related to substance metabolism, secreted protein and immune escape. Meanwhile, six antibiotic resistance genes (RbpA, tetA (33), erm (46), sul1, qacEdelta 1 and aadA9) were detected, and all strains carried RbpA related to rifamycin resistance. In addition, 28 plasmids were found in the 53 R. equi strains, belonging to Type-A (n = 14), Type-B (n = 8) and Type-N (n = 6), respectively. The genetic structures of the same type of plasmid were highly similar. In conclusion, R. equi strains show different genomic characteristics, virulence-related genes, potential drug resistance and virulence plasmid structures, which may be conducive to the evolution of its pathogenesis.

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Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific anti-YFV drugs are available till now. Here, we report that rifapentine is a potent YFV inhibitor in various cell lines by high-throughput drugs screening, acting at both cell entry and replication steps. Kinetic test and binding assay suggest that rifapentine interferes the viral attachment to the target cells. The application of YFV replicon and surface plasmon resonance assay indicates that rifapentine suppresses viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5. Further molecular docking suggests that it might interact with the active centre of RdRp. Rifapentine significantly improves the survival rate, alleviates clinical signs, and reduces virus load and injury in targeted organs both in YFV-infected type I interferon receptor knockout A129-/- and wild-type C57 mice. The antiviral effect in vivo is robust during both prophylactic intervention and therapeutic treatment, and the activity is superior to sofosbuvir, a previously reported YFV inhibitor in mice. Our data show that rifapentine may serve as an effective anti-YFV agent, providing promising prospects in the development of YFV pharmacotherapy.

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