ABSTRACT The World Health Organization (WHO) places Tuberculosis (TB) as one of the most important health problems today. According to the WHO, this disease requires novel actions to control its expansion and, in this way, achieve one of the goals established in the sustainable development goals: to reduce TB morbidity and incidence by 2030 and regain control. To achieve this goal, the tools currently used for diagnosis and treatment are no longer adequate. In this sense, it is necessary to develop new drugs and vaccines, as well as novel drug administration procedures that generate a better response, reduce times, and optimize treatments. Nanotechnology has incorporated in recent years a considerable number of new tools that significantly increase the diversity of mechanisms for the administration of anti-tuberculosis drugs. Therefore, the present review briefly describes the current state of drug resistance in tuberculosis, as well as the general characteristics of nanoparticles being evaluated as tools to transport new antibiotics against tuberculosis.

RESUMEN La Organización Mundial de la Salud (OMS) ubica a la tuberculosis (TB) como uno de los problemas de salud más preocupantes en la actualidad, y señala que se requieren de acciones novedosas para controlar su expansión y, de esta manera, alcanzar una de las metas establecidas en los Objetivos de Desarrollo Sostenible: reducir para 2030 la morbilidad e incidencia de TB. Para lograr este objetivo, está claro que las herramientas empleadas actualmente para su diagnóstico y tratamiento ya no son las adecuadas. En este sentido, es necesario desarrollar nuevos medicamentos y vacunas, así como novedosos procedimientos de administración de fármacos que generen una mejor respuesta, disminuyan el tiempo y optimicen los tratamientos. La nanotecnología ha incorporado en los últimos años un gran número de nuevas herramientas que incrementan considerablemente, la diversidad de mecanismos para la administración de tratamientos antituberculosos. Dicho esto, la presente revisión describe brevemente el estado actual de la farmacorresistencia en TB, así como las características generales de las nanopartículas que están evaluándose como herramientas para transportar antibióticos antituberculosos.

ABSTRACT The World Health Organization (WHO) places Tuberculosis (TB) as one of the most important health problems today. According to the WHO, this disease requires novel actions to control its expansion and, in this way, achieve one of the goals established in the sustainable development goals: to reduce TB morbidity and incidence by 2030 and regain control. To achieve this goal, the tools currently used for diagnosis and treatment are no longer adequate. In this sense, it is necessary to develop new drugs and vaccines, as well as novel drug administration procedures that generate a better response, reduce times, and optimize treatments. Nanotechnology has incorporated in recent years a considerable number of new tools that significantly increase the diversity of mechanisms for the administration of anti-tuberculosis drugs. Therefore, the present review briefly describes the current state of drug resistance in tuberculosis, as well as the general characteristics of nanoparticles being evaluated as tools to transport new antibiotics against tuberculosis.

RESUMEN La Organización Mundial de la Salud (OMS) ubica a la tuberculosis (TB) como uno de los problemas de salud más preocupantes en la actualidad, y señala que se requieren de acciones novedosas para controlar su expansión y, de esta manera, alcanzar una de las metas establecidas en los Objetivos de Desarrollo Sostenible: reducir para 2030 la morbilidad e incidencia de TB. Para lograr este objetivo, está claro que las herramientas empleadas actualmente para su diagnóstico y tratamiento ya no son las adecuadas. En este sentido, es necesario desarrollar nuevos medicamentos y vacunas, así como novedosos procedimientos de administración de fármacos que generen una mejor respuesta, disminuyan el tiempo y optimicen los tratamientos. La nanotecnología ha incorporado en los últimos años un gran número de nuevas herramientas que incrementan considerablemente, la diversidad de mecanismos para la administración de tratamientos antituberculosos. Dicho esto, la presente revisión describe brevemente el estado actual de la farmacorresistencia en TB, así como las características generales de las nanopartículas que están evaluándose como herramientas para transportar antibióticos antituberculosos.

Abstract In the present study we evaluated six α,β-unsaturated amides named piperlotines (for being isolated originally from Piper species) as new in vivo anti-inflammatory agents. In addition, we report the mechanosynthesis of two of them by mechanochemical activation of a Horner-Wadsworth-Emmons reaction. The reaction of β-amidophosphonate 4, an aromatic aldehyde and K2CO3 under grinding in a mortar and pestle afforded piperlotines 5-6 in good yields (70-88%) in short reaction times, obtaining only (E)-diastereomer. Piperlotines previously prepared were tested as anti-inflammatory and antibacterial agents. In this respect, derivatives 2 and 6 exhibited excellent in vivo anti-inflammatory activity on mice, especially trough topical administration (TPA acute inflammation model). Furthermore, piperlotine A, and compounds 2 and 6 had slight antimycobacterial activity against Mycobacterium tuberculosis (MIC = 50 µg/mL). In conclusion, the solvent-free mechanosynthesis of piperlotines produced valuable compounds that could serve as templates for further investigation in the search of better drug-like compounds for the treatment of inflammatory diseases.

Resumen En la presente investigación se evaluó la actividad anti-inflamatoria in vivo de seis amidas α,β-insaturadas, identificadas en la literatura como piperlotinas debido a su inicial aislamiento a partir de especies vegetales del género Piper (como las pimientas). La reacción del β-amidofosfonato 4 con un aldehído aromático y K2CO3 en molienda con mortero y pistilo produjo las piperlotinas 5-6 con buenos rendimientos (70-80%) en tiempos cortos de reacción, obteniendo solamente el diastereoisómero (E). Las piperlotinas preparadas se evaluaron como agentes anti-inflamatorios y antibacterianos, observando excelente actividad anti-inflamatoria para los derivados 2 y 6, especialmente cuando se probaron mediante administración tópica (modelo de inflamación aguda por TPA). Además, la piperlotina A y los derivados 2 y 6 mostraron actividad antibacteriana contra Mycobacterium tuberculosis (MIC = 50 µg/mL). En conclusión, la síntesis de piperlotinas a través de molienda en condiciones libres de disolvente generó importantes productos que pueden ser utilizados como punto de partida para generar nuevos compuestos bioactivos para el tratamiento de padecimientos relacionados con la inflamación.

Abstract The plasmid-encoded toxin (Pet) is one of the most studied Enterobacteriaceae autotransporters produced by the enteroaggregative Escherichia coli (EAEC). It is responsible of morphological changes in enterocytes during EAEC infection. Recently, Pet was found in the genome of the Proteus mirabilis RTX339 strain [P. mirabilis (Pet+)]. P. mirabilis causes complicated urinary tract infections (UTI) in patients having urinary catheters and structural or functional abnormalities. In this study, an UTI was induced in BALB/c female mice with the P. mirabilis (Pet+) strain. Mice infected by P. mirabilis (Pet+) showed bacterial colonization in bladder and kidney, from the second up to the tenth day post-infection. Morphological changes were evidenced by histology. Multiple exfoliated rounded cells were observed in the bladder transitional epithelium, as well as, structural cell alterations in the kidney cortex. The presence of Pet into exfoliated and parenchymal cells was confirmed by confocal microscopy. Cytoskeleton alterations were observed in those sites where Pet was detected. Pet expressed by P. mirabilis (Pet+) strain, contributes to its pathogenicity, affecting urinary tissues during the course of the infection.

Resumen La toxina Pet (plasmid-encoded toxin) producida por Escherichia coli (EAEC) es uno de los autotransportadores más estudiados en la familia Enterobacteriaceae. Es responsable de cambios morfológicos en enterocitos durante la infección por EAEC. Recientemente, Pet fue encontrada en el genoma de una cepa de Proteus mirabilis RTX339 [P. mirabilis (Pet+)]. P. mirabilis causa infección en el tracto urinario (ITU) en pacientes que usan catéteres o que presentan anomalías estructurales o funcionales. En este estudio una ITU con P. mirabilis (Pet+) fue inducida en ratones hembras BALB/c. Los ratones infectados con P. mirabilis (Pet+) muestran una colonización bacteriana en vejiga y riñón desde el segundo hasta el día decimo de la infección. Los cambios morfológicos fueron evidenciados por histología. Se observaron múltiples células exfoliadas del epitelio de transición de la vejiga, así como alteraciones morfológicas en la corteza renal. Se confirmó la presencia de Pet en las células exfoliadas y en las del parénquima por microscopía confocal. Las alteraciones del citoesqueleto fueron observadas en los sitios donde se detectó Pet. La toxina Pet expresada por la cepa de P. mirabilis (Pet+) contribuye a la patogenicidad y afecta tejidos urinarios durante el curso de la infección.

Moussonia deppeana is known as tlachichinole, clachichinole, etc. In Mexican traditional medicine is used to treat gastrointestinal disorders, cough, stomach and duodenal ulcers, kidney and vaginal infections. The organic extracts prepared by maceration were evaluated against 11 mycobacterial strains and three protozoal. The AcOEt extract was active against Mycobacterium tuberculosis H37Rv, etambutol-resistant of H37Rv, and the clinical isolate SIN4 showed MIC=12.5 μg/mL, and against MMDO showed an MIC = 25 μg/mL. The Hex extract resulted moderately active against ethambutol-resistant of H37Rv and clinical isolates SIN4 and MMDO (MIC = 25 μg/mL). The Hex, AcOEt, and EtOH extracts were inactive against non-tuberculous mycobacterium strains showed MIC >50 μg/mL and against Giardia lamblia, Entamoeba histolytica, and Trichomona vaginalis showed IC50 >200 μg/mL. M. deppeana biosynthesized compounds with antimycobacterial activity.

Moussonia deppeana es conocida como tlachichinole, clachichinole, etc. En la medicina tradicional de México se utiliza para tratar: padecimientos gastrointestinales, tos, úlceras estomacales y/o duodenales, infecciones renales y vaginales. Los extractos orgánicos fueron evaluados contra once cepas de micobacterias y tres parásitos. El extracto AcOEt resultó activo contra Mycobacterium tuberculosis H37Rv, H37Rv resistente a etambutol y contra el aislado clínico SIN4 (CMI = 12.5 μg/mL), contra MMDO mostró una CMI=25 μg/mL. El extracto Hex resultó moderadamente activo contra H37Rv resistente a etambutol y contra los aislados clínicos SIN4 y MMDO (CMI=25 μg/mL). Los extractos de Hex, AcOEt y EtOH resultaron inactivos contras las micobacterias no tuberculosas (CMI > 50 μg/mL) y contra Giardia lamblia, Entamoeba histolytica y Trichomona vaginalis mostrando IC50 >200 μg/mL. M. deppeana biosintetiza compuestos con actividad antimicobacteriana.

The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.

Tuberculosis (TB - Mycobacterium tuberculosis) is an ancient infectious disease that has appeared once again as a serious worldwide health problem and now comprises the second leading cause of death resulting from a single infection. The prevalence of multidrug resistance (MDR) TB is increasing and therapeutic options for treatment are not always accessible; in fact, some patients do not respond to the available drugs. Therefore, there is an urgent need to develop novel anti-TB agents. The aim of the present study was to screen extracts of Aristolochia taliscana, a plant used in traditional Mexican medicine to treat cough and snake bites, for antimycobacterial activity. The hexanic extract of A. taliscana was tested by microdilution alamar blue assay against Mycobacterium strains and bioguided fractionation led to the isolation of the neolignans licarin A, licarin B and eupomatenoid-7, all of which had antimycobacterial activity. Licarin A was the most active compound, with minimum inhibitory concentrations of 3.12-12.5 μg/mL against the following M. tuberculosis strains: H37Rv, four mono-resistant H37Rv variants and 12 clinical MDR isolates, as well as against five non-tuberculous mycobacteria (NTM) strains. In conclusion, licarin A represents a potentially active anti-TB agent to treat MDR M. tuberculosis and NTM strains.

The results on the bioevaluation of thirty five plant-derived secondary metabolites against one sensitive and three multidrug-resistant clinical isolates of Mycobacterium tuberculosis are reported. Results toward the sensitive strain showed that five products gave MIC values of 12.5 µg/mL: the alkaloids 6-methoxydihydrochelerytrine (2) and 6-methoxy-dihydrochelirubine (6), the flavanone pinostrobin (17), 1-hydroxy-benzoisochromanquinone (23) and 23-hydroxy-5a-lanosta-7,9(11),24-triene-3-one (33). These were followed by the peracetylstrictosidine lactam (12) and the quinone aloe-emodin (24) which displayed MICs of 6.25 µg/mL. Finally, liriodenine (8) was the most active (MIC: 3.125 µg/mL) of all secondary metabolites. Results with the multidrug-resistant clinical isolates showed that 6-methoxy-dihydrochelirubine (6) was the most active (MIC: 12.5 µg/mL).

Se informan los resultados sobre la bioevaluación de treinta y cinco metabolitos secundarios de plantas frente a una cepa sensible y a tres cepas resistentes a múltiples drogas de Mycobacterium tuberculosis. Los resultados frente a la cepa sensible mostraron que cinco metabolitos secundarios poseen valores de CMI de 12.5 µg/mL: los alcaloides 6-metoxidihidroqueleritrina (2) y 6-metoxi-dihidroque-lirubina (6), la flavanona pinostrobina (17), 1-hidroxi-benzoisocromanquinona (23) y el triterpeno 23-hidroxi-5a-lanosta-7,9(11),24-trien-3-ona (33). La lactama de peracetilestrictosidina (12) y la quinona aloe-emodina (24) mostraron CMIs de 6.25 µg/mL. Finalmente, liriodenina (8) fue la substancia mas activa (CMI: 3.125 µg/mL) de todos los metabolitos secundarios. Los resultados con los aislados clínicos resistentes a multidrogas mostraron que 6-metoxi-dihidroquelirubina (6) fue el compuesto mas activo (CMI: 12.5 µg/mL).