Nitric oxide-releasing prodrug for the treatment of complex Mycobacterium abscessus infections.

Non-tuberculosis mycobacteria (NTM) can cause severe respiratory infection in patients with underlying pulmonary conditions, and these infections are extremely difficult to treat. In this report, we evaluate a nitric oxide (NO)-releasing prodrug [methyl tris diazeniumdiolate (MD3)] against a panel of NTM clinical isolates and as a treatment for acute and chronic NTM infections in vivo. Its efficacy in inhibiting growth or killing mycobacteria was explored in vitro alongside evaluation of the impact to primary human airway epithelial tissue. Airway epithelial tissues remained viable after exposure at concentrations of MD3 needed to kill mycobacteria, with no inherent toxic effect from drug scaffold after NO liberation. Resistance studies conducted via serial passage with representative Mycobacterium abscessus isolates demonstrated no resistance to MD3. When administered directly into the lung via intra-tracheal administration in mice, MD3 demonstrated significant reduction in M. abscessus bacterial load in both acute and chronic models of M. abscessus lung infection. In summary, MD3 is a promising treatment for complex NTM pulmonary infection, specifically those caused by M. abscessus, and warrants further exploration as a therapeutic.

Rapid Mycobacterium abscessus antimicrobial susceptibility testing based on antibiotic treatment response mapping via Raman Microspectroscopy.

OBJECTIVES: Antimicrobial susceptibility tests (ASTs) are pivotal tools for detecting and combating infections caused by multidrug-resistant rapidly growing mycobacteria (RGM) but are time-consuming and labor-intensive. DESIGN: We used a Mycobacterium abscessus-based RGM model to develop a rapid (24-h) AST from the beginning of the strain culture, the Clinical Antimicrobials Susceptibility Test Ramanometry for RGM (CAST-R-RGM). The ASTs obtained for 21 clarithromycin (CLA)-treated and 18 linezolid (LZD)-treated RGM isolates. RESULTS: CAST-R-RGM employs D2O-probed Raman microspectroscopy to monitor RGM metabolic activity, while also revealing bacterial antimicrobial drug resistance mechanisms. The results of clarithromycin (CLA)-treated and linezolid (LZD)-treated RGM isolates exhibited 90% and 83% categorical agreement, respectively, with conventional AST results of the same isolates. Furthermore, comparisons of time- and concentration-dependent Raman results between CLA- and LZD-treated RGM strains revealed distinct metabolic profiles after 48-h and 72-h drug treatments, despite similar profiles obtained for both drugs after 24-h treatments. CONCLUSIONS: Ultimately, the rapid, accurate, and low-cost CAST-R-RGM assay offers advantages over conventional culture-based ASTs that warrant its use as a tool for improving patient treatment outcomes and revealing bacterial drug resistance mechanisms.

Impaired ESX-3 Induces Bedaquiline Persistence in Mycobacterium abscessus Growing Under Iron-Limited Conditions.

ESX-3 is a secretion pathway which is essential for mycobactin-mediated iron acquisition under iron-limited conditions. Although present in all Mycobacterium sp., ESX-3 remains to be elucidated in Mycobacterium abscessus. In the study reported here, impaired ESX-3 seriously restricts the growth of M. abscesses under iron-limited conditions; growth is salvaged by functional ESX-3 or iron supplementation. Notably, impaired ESX-3 does not kill M. abscesses when environmental iron is insufficient but induces persistence to bedaquiline, a diarylquinoline class antibiotic used to treat multidrug-resistant mycobacteria. One potential mechanism contributing to persistence is the iron deficiency due to impaired ESX-3 suppressing succinate dehydrogenase activity, which dysregulates the tricarboxylic acid cycle and inactivates bedaquiline. Experiments conducted here also demonstrate that the regulator, MtrA, can bind ESX-3 and promote the survival of M. abscessus. As such, this study suggests that a novel pathway involving MtrA, ESX-3, iron metabolism, and the TCA cycle contributes to bedaquiline persistence in M. abscesses growing under iron-limited conditions.

Evaluation of the anti-mycobacterial activity and composition of Carlina acaulis L. root extracts.

Nontuberculous mycobacteria (NTM) have recently emerged as important bacterial pathogens of animals and humans. Of particular concern is the high level of antimicrobial resistance displayed by these organisms, which complicates treatment and potential successful outcomes. Here, we evaluated the potential of Carlina acaulis L. as a source of novel anti-mycobacterial agents. Our goal was to measure the activity of aqueous, ethanol, and chloroform C. acaulis root extracts against 99 NTM strains. GC-MS spectroscopy analyses were performed to deliver qualitative and quantitative data on the composition of C. acaulis extract. In our study, we have shown for the first time the activity of C. acaulis extracts against NTM. The highest activity was exhibited by the chloroform extract, which inhibited the growth of more than 90% of the strains at the dose of 100 µg/mL (MIC90 = 100 µg/mL). The results of the GC-MS analysis of the C. acaulis chloroform extract contributed to the identification of 37 compounds, with carlina oxide as the most representative compound (69.52%) followed by 3,4-dihydro-2H-phenanthren- -1-one (6.54%) and stigmast-5-en-3-ol (4.14%). Our results indicate that C. acaulis chloroform and ethanol extracts have potential for treatment of NTM infections and that this plant contains anti-mycobacterial compounds.

Loop pathways are responsible for tuning the accumulation of C19- and C22-sterol intermediates in the mycobacterial phytosterol degradation pathway.

4-Androstene-3,17-dione (4-AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (BA) are the most important and representative C19- and C22-steroidal materials. The optimalization of sterol production with mycobacterial phytosterol conversion has been investigated for decades. One of the major challenges is that current industrial mycobacterial strains accumulate unignorable impurities analogous to desired sterol intermediates, significantly hampering product extractions and refinements. Previously, we identified Mycobacterium neoaurum HGMS2 as an efficient 4-AD-producing strain (Wang et al. in Microb Cell Fact. 19:187, 2020). Recently, we have genetically modified the HGMS2 strain to remove its major impurities including ADD and 9OH-AD (Li et al. in Microb Cell Fact. 20:158, 2021). Unexpectedly, the modified mutants started to significantly accumulate BA compared with the HGMS2 strain. In this work, while we attempted to block BA occurrence during 4-AD accumulation in HGMS2 mutants, we identified a few loop pathways that regulated metabolic flux switching between 4-AD and BA accumulations and found that both the 4-AD and BA pathways shared a 9,10-secosteroidial route. One of the key enzymes in the loop pathways was Hsd4A1, which played an important role in determining 4-AD accumulation. The inactivation of the hsd4A1 gene significantly blocked the 4-AD metabolic pathway so that the phytosterol degradation pathway flowed to the BA metabolic pathway, suggesting that the BA metabolic pathway is a complementary pathway to the 4-AD pathway. Thus, knocking out the hsd4A1 gene essentially made the HGMS2 mutant (HGMS2Δhsd4A1) start to efficiently accumulate BA. After further knocking out the endogenous kstd and ksh genes, an HGMS2Δhsd4A1 mutant, HGMS2Δhsd4A1/Δkstd1, enhanced the phytosterol conversion rate to BA in 1.2-fold compared with the HGMS2Δhsd4A1 mutant in pilot-scale fermentation. The final BA yield increased to 38.3 g/L starting with 80 g/L of phytosterols. Furthermore, we knocked in exogenous active kstd or ksh genes to HGMS2Δhsd4A1/Δ kstd1 to construct DBA- and 9OH-BA-producing strains. The resultant DBA- and 9OH-BA-producing strains, HGMS2Δhsd4A1/kstd2 and HGMS2Δkstd1/Δhsd4A1/kshA1B1, efficiently converted phytosterols to DBA- and 9OH-BA with the rates of 42.5% and 40.3%, respectively, and their final yields reached 34.2 and 37.3 g/L, respectively, starting with 80 g/L phytosterols. Overall, our study not only provides efficient strains for the industrial production of BA, DBA and 9OH-BA but also provides insights into the metabolic engineering of the HGMS2 strain to produce other important steroidal compounds.

Potential Use of Mycobacterium paragordonae for Antimycobacterial Drug Screening Systems.

Our recent genome-based study indicated that Mycobacterium paragordonae (Mpg) has evolved to become more adapted to an intracellular lifestyle within free-living environmental amoeba and its enhanced intracellular survival within Acanthamoeba castellanii was also proved. Here, we sought to investigate potential use of Mpg for antimycobacterial drug screening systems. Our data showed that Mpg is more susceptible to various antibiotics compared to the close species M. marinum (Mmar) and M. gordonae, further supporting its intracellular lifestyle in environments, which would explain its protection from environmental insults. In addition, we developed two bacterial whole-cell-based drug screening systems using a recombinant Mpg stain harboring a luciferase reporter vector (rMpg-LuxG13): one for direct application to rMpg-LuxG13 and the other for drug screening via the interaction of rMpg-LuxG13 with A. castellanii. Direct application to rMpg-LuxG13 showed lower inhibitory concentration 50 (IC50) values of rifampin, isoniazid, clarithromycin, and ciprofloxacin against Mpg compared to Mmar. Application of drug screening system via the interaction of rMpg-LuxG13 with A. castellanii also exhibited lower IC50 values for rifampin against Mpg compared to Mmar. In conclusion, our data indicate that Mpg is more susceptible to various antibiotics than other strains. In addition, our data also demonstrate the feasibility of two whole cell-based drug screening systems using rMpg-LuxG13 strain for the discovery of novel anti-mycobacterial drugs.

Levantamento epidemiológico dos casos de tuberculose no Brasil e ações alternativas para auxiliar no tratamento / Epidemiological survey of tuberculosis cases in Brazil and alternative actions to aid in treatment / Estudio epidemiológico de los casos de tuberculosis en Brasil y acciones alternativas para ayudar al tratamiento

tuberculose é uma das doenças infectocontagiosas de maior importância no Brasil e no mundo. Afeta de forma importante populações em situação de vulnerabilidade social e econômica. O objetivo deste estudo foi realizar um levantamento do número de casos notificados de tuberculose no Brasil nos últimos 10 anos (2011 a 2021), avaliar os fatores que afetam a transmissão, bem como discutir o tratamento padrão e com fitoterápicos. O levantamento epidemiológico dos casos de tuberculose no Brasil de janeiro de 2011 a dezembro de 2021 foi realizado dentre os notificados pelo Sistema de Informação de Agravos de Notificação (SINAN). Os resultados indicaram um aumento linear de casos a partir de 2017 com 90.776 casos diagnosticados, em 2018 (94.720) e 2019 (96.655). Acredita-se que o aumento linear da tuberculose neste período pode estar relacionado principalmente com o aumento da pobreza, contudo o compartilhamento de utensílios durante o uso de narguilé podem representar fatores de risco para tuberculose. Seis plantas medicinais afetam diretamente as micobactérias (Chenopodium ambrosioides, Tetradenia riparia, Physalis angulata, Origanum vulgare, Eucalyptus globulus, Mikania glomerata) e cinco plantas com atividade antibacteriana auxiliam no trato respiratório (Nasturtium officinale, Allium sativum, Schinus terebinthifolius, Adiantum capillus-veneris, Allium cepa). Contudo, a tuberculose é uma doença reemergente sendo necessária a adoção de políticas públicas que intensifiquem e implementem medidas sócio-educativas para a implantação do uso de fitoterápicos como medida complementar.

Tuberculosis is one of the most important infectious diseases in Brazil and worldwide. It significantly affects populations in situations of social and economic vulnerability. This study aimed to survey the number of reported tuberculosis cases in Brazil in the last 10 years (2011 to 2021) to assess the factors that affect the transmission and discuss standard and herbal treatments. The epidemiological survey of tuberculosis cases in Brazil from January 2011 to December 2021 was carried out among those notified by the Notifiable Diseases Information System (SINAN). The results indicated a linear increase in cases from 2017, with 90,776 diagnosed cases, in 2018 (94,720) and 2019 (96,655). It is believed that the linear increase in tuberculosis in this period may be mainly related to the increase in poverty. However, the sharing of utensils during the use of hookah may represent risk factors for tuberculosis. Six medicinal plants directly affect mycobacteria (Chenopodium ambrosioides, Tetradenia riparia, Physalis angulata, Origanum vulgare, Eucalyptus globulus, Mikania glomerata), and five plants with antibacterial activity help in the respiratory tract (Nasturtium officinale, Allium sativum, Schinus terebinthifolius, Adiantum capillus-veneris, Allium cepa). However, tuberculosis is a re-emerging disease, and it is necessary to adopt public policies that intensify and implement socio-educational measures for using herbal medicines as a complementary measure.

La tuberculosis es una de las enfermedades infecciosas más importantes en Brasil y en el mundo. Afecta significativamente a las poblaciones en situación de vulnerabilidad social y económica. El objetivo de este estudio fue realizar una encuesta sobre el número de casos notificados de tuberculosis en Brasil en los últimos 10 años (2011 a 2021), para evaluar los factores que afectan a la transmisión, así como para discutir el tratamiento estándar y con fitoterapias. La encuesta epidemiológica de los casos de tuberculosis en Brasil desde enero de 2011 hasta diciembre de 2021 se realizó entre los notificados por el Sistema de Informação de Agravos de Notificação (SINAN). Los resultados indicaron un aumento lineal de casos desde 2017 con 90.776 casos diagnosticados, en 2018 (94.720) y 2019 (96.655). Se cree que el aumento lineal de la tuberculosis en este periodo puede estar relacionado principalmente con el aumento de la pobreza, aunque el hecho de compartir los utensilios durante el uso de la shisha puede representar factores de riesgo para la tuberculosis. Seis plantas medicinales afectan directamente a las micobacterias (Chenopodium ambrosioides, Tetradenia riparia, Physalis angulata, Origanum vulgare, Eucalyptus globulus, Mikania glomerata) y cinco plantas con actividad antibacteriana ayudan a las vías respiratorias (Nasturtium officinale, Allium sativum, Schinus terebinthifolius, Adiantum capillus-veneris, Allium cepa). Sin embargo, la tuberculosis es una enfermedad reemergente siendo necesaria la adopción de políticas públicas que intensifiquen e implementen medidas socioeducativas para la implementación del uso de fitoterápicos como medida complementaria.

In vitro synergy between manuka honey and amikacin against Mycobacterium abscessus complex shows potential for nebulisation therapy.

Mycobacterium abscessusis an opportunistic human pathogen of increasing concern, due to its ability to cause aggressive pulmonary infections (especially in cystic fibrosis patients), as well as skin and soft tissue infections. M. abscessus is intrinsically drug resistant and treatment regimens are lengthy, consisting of multiple antibiotics with severe side effects and poor patient success rates. New and novel strategies are urgently required to combat these infections. One such strategy thus far overlooked for mycobacteria is manuka honey. For millennia manuka honey has been shown to have wide ranging medicinal properties, which have more recently been identified for its broad spectrum of antimicrobial activity. Here we demonstrate that manuka honey can be used to inhibit M. abscessus and a variety of drug resistant clinical isolates in vitro. We also demonstrate using a microbroth dilution checkerboard assay that manuka honey works synergistically with amikacin, which is one of the current front line antibiotics used for treatment of M. abscessus infections. This was further validated using an in vitro inhalation model, where we showed that with the addition of manuka honey, the amikacin dosage can be lowered whilst increasing its efficacy. These findings demonstrate the utility of manuka honey for incorporation into nebulised antibiotic treatment for respiratory infections, in particular M. abscessus. These results pave the way for a change of strategy for M. abscessus management, offering new therapeutic options for this deadly infection.

Metabolic Processing of Selenium-Based Bioisosteres of meso-Diaminopimelic Acid in Live Bacteria.

A primary component of all known bacterial cell walls is the peptidoglycan (PG) layer, which is composed of repeating units of sugars connected to short and unusual peptides. The various steps within PG biosynthesis are targets of potent antibiotics as proper assembly of the PG is essential for cellular growth and survival. Synthetic mimics of PG have proven to be indispensable tools to study the bacterial cell structure, growth, and remodeling. Yet, a common component of PG, meso-diaminopimelic acid (m-DAP) at the third position of the stem peptide, remains challenging to access synthetically and is not commercially available. Here, we describe the synthesis and metabolic processing of a selenium-based bioisostere of m-DAP (selenolanthionine) and show that it is installed within the PG of live bacteria by the native cell wall crosslinking machinery in mycobacterial species. This PG probe has an orthogonal release mechanism that could be important for downstream proteomics studies. Finally, we describe a bead-based assay that is compatible with high-throughput screening of cell wall enzymes. We envision that this probe will supplement the current methods available for investigating PG crosslinking in m-DAP-containing organisms.

Investigation of drug regimens and treatment outcome in patients with Mycobacterium Simiae: a systematic review.

INTRODUCTION: Mycobacterium simiae (M.simiae), a non-tuberculous mycobacterium (NTM), rare causes infection including localized pulmonary to disseminated disease in immunocompromised patients. An optimal pharmacological management practice has not yet been defined for this infection. This study investigates drug regimens and treatment outcomes in patients with M. simiae to describe different drug regimen with the therapeutic response. AREAS COVERED: The three databases PubMed, Scopus, and Web of science were systematically searched from June 1994 to June 2021 to retrieve relevant articles. The inclusion criterion included studies, which reported treatment outcomes in patients with M. simiae infections. Treatment success was defined as the achievement of culture conversion, and the improvement of the symptoms and radiologic signs among the patients. EXPERT OPINION: Data of 223 patients were retrieved from 40 studies. Duration of the treatment regimens used in different studies ranged from 2 to 12 months. The most common treatment regimens administered for M. simiae infection were as follows: clarithromycin, rifampin, ethambutol, moxifloxacin, or ciprofloxacin and amikacin plus cotrimoxazole or pyrazinamide in some regimens. Macrolides, such as clarithromycin, combined with quinolones (such as moxifloxacin) and TMP/SMX, which are used in combination, had the most significant effect on eliminating the pulmonary signs of M. simiae.

Antibacterial Activity of Pharmaceutical-Grade Rose Bengal: An Application of a Synthetic Dye in Antibacterial Therapies.

Rose bengal has been used in the diagnosis of ophthalmic disorders and liver function, and has been studied for the treatment of solid tumor cancers. To date, the antibacterial activity of rose bengal has been sporadically reported; however, these data have been generated with a commercial grade of rose bengal, which contains major uncontrolled impurities generated by the manufacturing process (80-95% dye content). A high-purity form of rose bengal formulation (HP-RBf, >99.5% dye content) kills a battery of Gram-positive bacteria, including drug-resistant strains at low concentrations (0.01-3.13 µg/mL) under fluorescent, LED, and natural light in a few minutes. Significantly, HP-RBf effectively eradicates Gram-positive bacterial biofilms. The frequency that Gram-positive bacteria spontaneously developed resistance to HP-RB is extremely low (less than 1 × 10-13). Toxicity data obtained through our research programs indicate that HP-RB is feasible as an anti-infective drug for the treatment of skin and soft tissue infections (SSTIs) involving multidrug-resistant (MDR) microbial invasion of the skin, and for eradicating biofilms. This article summarizes the antibacterial activity of pharmaceutical-grade rose bengal, HP-RB, against Gram-positive bacteria, its cytotoxicity against skin cells under illumination conditions, and mechanistic insights into rose bengal's bactericidal activity under dark conditions.

Challenges in Treating Mycobacterium chelonae/abscessus Prosthetic Joint Infection.

Prosthetic joint infections (PJIs) remain a major complication of arthroplasty, most of which are caused by Staphylococcus aureus and gram-negative bacteria. Unfortunately, cultures are false negative in upward of 7 percent of patients with suspected PJIs, and commonly in infections caused by rare rapidly growing mycobacterium (RGM) species. Guidelines recommend 6 months of antimycobacterial therapy for bone diseases caused by RGM, with empiric therapy consists of an oral macrolide (clarithromycin or azithromycin) plus tobramycin and imipenem-cilastatin. Definitive treatment of PJI due to RGM should be guided by antimicrobial susceptibility, however, most microbiology laboratories are unable to differentiate between M. chelonae and M. abscessus. Furthermore, treatment of M. chelonae PJI is challenging due to multidrug resistance and the dearth of oral antibiotics for therapy. This case report investigates a patient with PJI caused by M. chelonae and M. abscessus. The initial treatment with imipenem-cilastatin was complicated by drug induced seizures, further limiting therapy options.

Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis.

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)-an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO-control, AIA-untreated adjuvant-induced arthritis, AIA-BIL-adjuvant-induced arthritis administrated UCB, CO-BIL-control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund's adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.

Modulation of a Mycobacterial ADP-Ribosyltransferase to Augment Rifamycin Antibiotic Resistance.

The rifamycins are broad-spectrum antibiotics that are primarily utilized to treat infections caused by mycobacteria, including tuberculosis. Interestingly, various species of bacteria are known to contain an enzyme called Arr that catalyzes ADP-ribosylation of rifamycin antibiotics as a mechanism of resistance. Here, we study Arr modulation in relevant Gram-positive and -negative species. We show that a C-terminal truncation of Arr (ArrC), encoded in the genome of Mycobacterium smegmatis, activates Arr-mediated rifamycin modification. Through structural comparisons of mycobacterial Arr and human poly(ADP-ribose) polymerases (PARPs), we identify a known small molecule PARP inhibitor that can act as an adjuvant to sensitize M. smegmatis to the rifamycin antibiotic rifampin via inhibition of Arr, even in the presence of ArrC. Finally, we demonstrate that this rifampin/adjuvant combination treatment is effective at inhibiting growth of the multidrug-resistant (MDR) nontuberculosis pathogen Mycobacterium abscessus, which has become a growing cause of human infections in the clinic.

Phytochemical analysis and evaluation of antioxidant and antimycobacterial activity of Colletia paradoxa from Brazil.

Colletia paradoxa (Spreng.) Esc. (Rhamnaceae, Colletieae) is a medicinal plant, threatened with extinction in Brazil, presenting great morphological variability. Our objective is to investigate the phytochemical components, antioxidant capacity and antimycobacterial activity of different morphotypes of C. paradoxa in different environments. For this, the crude extract of the leaves and branches of the individuals sampled was used. The elimination capacity of the free radicals was determined by the DPPH method, the antimycobacterial activity by the broth microdilution method and the phenolic content by the spectrophotometric method using the Folin-Ciocalteu reagent and by HPLC. The extracts of C. paradoxa and its morphotypes showed significant amounts of phenolic compounds, including quercetin, quercitrin and rutin, besides considerable antioxidant and antimycobacterial activity No connection was detected between the phytochemical composition and different morphotypes of C. paradoxa.

'TB or not TB': the conundrum of pre-European contact tuberculosis in the Pacific.

Tuberculosis (TB) is a major global health threat, infecting one-third of the world's population. Despite this prominence, the age, origin and spread of the disease have been topics of contentious debate. Molecular studies suggest that Mycobacterium tuberculosis 'sensu stricto', the most common strain of TB infecting humans today, originated in Africa and from there spread into Europe and Asia. The M. tuberculosis strains most commonly found across the Pacific and the Americas today are most closely related to European strains, supporting a hypothesis that the disease only reached these regions relatively recently via European sailors or settlers. However, this hypothesis is inconsistent with palaeopathological evidence of TB-like lesions in human remains from across the Pacific that predate European contact. Similarly, genetic evidence from pre-European South American mummies challenges the notion of a European introduction of the disease into the Pacific. Here, we review the complex evidence for the age and origin of TB in the Pacific, and discuss key gaps in our knowledge and how these may be addressed. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.

Glycyrrhizic acid facilitates anti-tumor immunity by attenuating Tregs and MDSCs: An immunotherapeutic approach.

Melanoma is one of the most aggressive malignancies and its treatment remains challenging due to its highly metastatic property and availability of limited effective drugs. In addition, immunosuppresive tumor microenvironment (TME) has been identified as major barrier to evoke anti-tumor response in melanoma. Recent studies revealed that immunosuppressive TME is directly correlated with heightened activations of T regulatory cells (Tregs) and Myeloid derived suppressor cells (MDSCs) functions. In this study, we investigated the anti-cancer effect of a triterpenoid, glycyrrhizic acid (GA) on melanoma. Our study revealed that GA not only exhibited anti-proliferative effects on melanoma cells it significantly restricted progression of melanoma tumor. However, the therapeutic efficacy of GA in impressive regression of tumor was found to be directly correlated with induction of apoptosis and modulation of cytokines from Th2 to Th1 type. To unravel the mechanism of anti-melanoma effect of GA, it has been delineated that GA inhibits pSTAT3 to evade anti-tumor suppressive function of Tregs and MDSCs. Downregulation of FOXP3, GITR and CTLA4 in tumor-infiltrating Tregs and inhibition of Cox2, PGE2 and Arginase 1 in intra-tumoral MDSC were evidenced as some of the key events during therapeutic intervention of GA in melanoma management. Moreover, GA effectively restricted advanced stage solid tumor while used in combination with Mycobacterium indicus pranii, a known immunomodulator, which alone is reported to be ineffective to restrict advanced stage solid tumor. Thus, our findings may open up a novel insight of GA as a promising agent in cancer immunotherapy or adjuvant therapy in future.

Cutaneous infection by Mycobacterium lentiflavum after subcutaneous injection of lipolytic formula

Abstract The incidence of nontuberculous mycobacterial infections is increasing worldwide; by 2017, more than 190 species and subspecies have been documented. Although classically associated with immunosuppression, the recognition of these etiological agents in diseases affecting immunocompetent individuals and in healthcare-associated infections, such as after surgical and cosmetic procedures, makes the study of the epidemiology and pathogenesis of these microorganisms relevant in medical practice. Mycobacterium lentiflavum is slow-growing and rarely affects the skin. A case of cutaneous mycobacteriosis caused by M. lentiflavum is reported in an immunocompetent patient after subcutaneous injection of a lipolytic compound, treated with clarithromycin and levofloxacin.

Cutaneous infection by Mycobacterium lentiflavum after subcutaneous injection of lipolytic formula.

The incidence of nontuberculous mycobacterial infections is increasing worldwide; by 2017, more than 190 species and subspecies have been documented. Although classically associated with immunosuppression, the recognition of these etiological agents in diseases affecting immunocompetent individuals and in healthcare-associated infections, such as after surgical and cosmetic procedures, makes the study of the epidemiology and pathogenesis of these microorganisms relevant in medical practice. Mycobacterium lentiflavum is slow-growing and rarely affects the skin. A case of cutaneous mycobacteriosis caused by M. lentiflavum is reported in an immunocompetent patient after subcutaneous injection of a lipolytic compound, treated with clarithromycin and levofloxacin.

Structure-activity relationship analyses of fusidic acid derivatives highlight crucial role of the C-21 carboxylic acid moiety to its anti-mycobacterial activity.

Fusidic acid (FA) is a potent congener of the fusidane triterpenoid class of antibiotics. Structure-activity relationship (SAR) studies suggest the chemical structure of FA is optimal for its antibacterial activity. SAR studies from our group within the context of a drug repositioning approach in tuberculosis (TB) suggest that, as with its antibacterial activity, the C-21 carboxylic acid group is indispensable for its anti-mycobacterial activity. Further studies have led to the identification of 16-deacetoxy-16ß-ethoxyfusidic acid (58), an analog which exhibited comparable activity to FA with an in vitro MIC99 value of 0.8 µM. Preliminary SAR studies around the FA scaffold suggested that the hydrophobic side chain at C-20, like the C-11 OH group, was required for activity. The C-3 OH group, however, can be functionalized to obtain more potent compounds.