Pre-detection history of #XDR #tuberculosis in #KwaZulu-Natal, South Africa (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Tyler S. Brown, Lavanya Challagundla, Evan H. Baugh, Shaheed Vally Omar, Arkady Mustaev, Sara C. Auld, N. Sarita Shah, Barry N. Kreiswirth, James C. M. Brust, Kristin N. Nelson, Apurva Narechania, Natalia Kurepina, Koleka Mlisana, Richard Bonneau, Vegard Eldholm, Nazir Ismail, Sergios-Orestis Kolokotronis, D. Ashley Robinson, Neel R. Gandhi, and Barun Mathema

PNAS first published October 28, 2019 / DOI:

Edited by Erwin Schurr, McGill University, Montreal, QC, Canada, and accepted by Editorial Board Member Carl F. Nathan October 3, 2019 (received for review April 17, 2019)



Epidemics of AMR pathogens are often only identified years or decades after they first evolved and distant from their place of origin. Consequently, evidence-based strategies for early containment of AMR epidemics are limited. This study employs whole-genome sequence data to reconstruct the “pre-detection” evolutionary and epidemiological history of an extensively drug-resistant Mycobacterium tuberculosis strain in KwaZulu-Natal, South Africa. We localize the geographic origin of this strain to an area hundreds of kilometers away from where the first clinical cases were reported and identify key host- and pathogen-specific factors that contributed to the rise of this important threat to global tuberculosis control. We propose that similar strategies can support the early identification and containment of AMR pathogens in the future.



Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.

infectious disease – epidemics – tuberculosis – antimicrobial resistance – population genetics

Keywords: Antibiotics; Drugs Resistance; Rifampin; XDR-TB; Mycobacterium tuberculosis; TB; South Africa.


#Prophylaxis of Mycobacterium #tuberculosis H37Rv #Infection in a Preclinical Mouse Model via Inhalation of Nebulized #Bacteriophage D29 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Prophylaxis of Mycobacterium tuberculosis H37Rv Infection in a Preclinical Mouse Model via Inhalation of Nebulized Bacteriophage D29

Nicholas B. Carrigy, Sasha E. Larsen, Valerie Reese, Tiffany Pecor, Melissa Harrison, Philip J. Kuehl, Graham F. Hatfull, Dominic Sauvageau, Susan L. Baldwin, Warren H. Finlay, Rhea N. Coler, Reinhard Vehring

DOI: 10.1128/AAC.00871-19



Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially-available vaccine that is sufficiently effective at preventing acquisition of pulmonary tuberculosis in adults. In this study, pre-exposure prophylactic pulmonary delivery of active aerosolized anti-tuberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. An average bacteriophage concentration of approximately 1 PFU/alveolus was achieved in the lungs of mice using a nose-only inhalation device optimized with a dose simulation technique and adapted for use with a vibrating mesh nebulizer. Within 30 minutes of bacteriophage delivery, the mice received either a low dose (∼50-100 CFU), or an ultra-low dose (∼5-10 CFU), of M. tuberculosis H37Rv aerosol to the lungs. A prophylactic effect was observed with bacteriophage aerosol pre-treatment significantly decreasing M. tuberculosis burden in mouse lungs 24 hours and 3 weeks post-challenge (p < 0.05). These novel results indicate that a sufficient dose of nebulized mycobacteriophage aerosol to the lungs may be a valuable intervention to provide extra protection to health care professionals and other individuals at risk of exposure to M. tuberculosis.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Mycobacterium tuberculosis; Bacteriophages; Animal models.


Effectiveness of #BCG #vaccination against Mycobacterium #tuberculosis #infection in #adults: a cross-sectional analysis of a #UK-based cohort (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: a cross-sectional analysis of a UK-based cohort

Anthea L Katelaris, Charlotte Jackson, Jo Southern, Rishi K Gupta,Francis Drobniewski, Ajit Lalvani, Marc Lipman, Punam Mangtani, Ibrahim Abubakar

The Journal of Infectious Diseases, jiz430,

Published: 29 August 2019




BCG appears to reduce acquisition of Mycobacterium tuberculosis (Mtb) infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of Mtb infection in adults.


We conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored.


Of 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (aOR=0.70, 95% CI 0.56-0.87, p=0.0017) yielding a VE of 30%. VE declined with time since vaccination, but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with non-vaccinated participants.


BCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against Mtb infection as well as disease. This has implications for immunisation programmes, vaccine development and tuberculosis control efforts worldwide.

BCG, Bacille Calmette-Guérin vaccine, tuberculosis, vaccine effectiveness

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© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail:

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Keywords: Mycobacterium tuberculosis; Vaccines; BCG.


Live-attenuated Mycobacterium #tuberculosis #vaccine MTBVAC versus #BCG in #adults and #neonates: a randomised controlled, double-blind dose-escalation trial (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Michele Tameris, MBChB *, Helen Mearns, PhD *, Adam Penn-Nicholson, PhD, Yolande Gregg, NDip, Nicole Bilek, PhD, Simbarashe Mabwe, BSc, Hennie Geldenhuys, MBChB, Justin Shenje, MBChB, Angelique Kany Kany Luabeya, MBChB, Ingrid Murillo, BD, Juana Doce, PhD, Nacho Aguilo, PhD, Dessislava Marinova, PhD, Eugenia Puentes, PhD, Esteban Rodríguez, VD, Jesús Gonzalo-Asensio, PhD, Bernard Fritzell, MD, Jelle Thole, PhD, Prof Carlos Martin, MD, Prof Thomas J Scriba, DPhil †, Prof Mark Hatherill, MD  † and theMTBVAC Clinical Trial Team

Published: August 12, 2019 / DOI:




Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high.


We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-γ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 10 5colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 10 5 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 10 5 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 10 3 CFU, 2·5 × 10 4 CFU, and 2·5 × 10 5 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with, number NCT02729571.


Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 10 3 CFU MTBVAC group, nine to the 2·5 × 10 4 CFU group, and ten to the 2·5 × 10 5 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 10 5 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 10 3 CFU MTBVAC group, two in the 2·5 × 10 4 CFU MTBVAC group, and two in the 2·5 × 10 5 CFU MTBVAC group), including one infant in the 2·5 × 10 3 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 10 5 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 10 3 CFU MTBVAC group, six (75%) of eight in the 2·5 × 10 4 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 10 3 CFU MTBVAC group, four (67%) of the six in the 2·5 × 10 4 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 10 5 CFU MTBVAC group.


MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition.


Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri.

Keywords: Tuberculosis; Vaccines; BCG.


Identifying regimens containing a new #drug candidate TBI-166 against #Mycobacterium tuberculosis in vitro and in vivo (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Identifying regimens containing a new drug candidate TBI-166 against Mycobacterium tuberculosis in vitro and in vivo

Ye Zhang, Hui Zhu, Lei Fu, Bin Wang, Shaochen Guo, Xi Chen, Zhongquan Liu, Haihong Huang, Tianjian Yang, Yu Lu

DOI: 10.1128/AAC.02496-18



TBI-166, derived from riminophenazine analogues, is under development in phase I clinical trial in China. TBI-166 showed more potent anti-TB activity than clofazimine in vitro and animal experiments. To identify potent regimens containing TBI-166 in TB chemotherapy, TBI-166 was assessed for pharmacological interactions in vitro and in vivo with several antituberculosis drugs, including isoniazid (INH), rifampin (RFP), bedaquiline (BDQ), pretomanid (PMD), linezolid (LZD), and pyrazinamide (PZA). Using the in vitro checkerboard method, TBI-166 did not show antagonism or synergy with the tested drugs. The interaction relationship between TBI-166 and each drug was indifferent. In vivo experiments, aerosol infection models with BALB/c and C3HeB/FeJNju mice were established, testing drugs were administered either individually or combined containing TBI-166 and 1-, 2-, or 3- other drugs, and the bactericidal activities were determined after 4- and 8-week therapeutic treatments. In BALB/c mice, five TBI-166 containing regimens, TBI-166+BDQ, TBI-166+PZA, TBI-166+BDQ+LZD, TBI-166+BDQ+PMD and TBI-166+BDQ+PMD+LZD showed significantly more potent efficacy after 4-week treatment compared with control regimen, INH+RFP+PZA. At the end of 8-week treatment, lung log CFU counts reached below detectable level in mice treated with each of the five regimens. The rank order of the potency of the five regimens were TBI-166+BDQ+LZD > TBI-166+BDQ > TBI-166+PZA > TBI-166+BDQ+PMD+LZD > TBI-166+BDQ+PMD. In C3HeB/FeJNju mice, TBI-166+BDQ+LZD was also the most effective one in TBI-166-containing regimens. In conclusion, five potent chemotherapy regimens containing TBI-166 were identified. The regimen TBI-166+BDQ+LZD is recommended to be tested in TBI-166 phase IIb clinical trial.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Mycobacterium tuberculosis.


#Drug susceptibility #testing and #mortality in patients treated for #tuberculosis in high-burden countries: a multicentre cohort study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries: a multicentre cohort study

Kathrin Zürcher, MSc *, Marie Ballif, PhD *, Prof Lukas Fenner, MD, Sonia Borrell, PhD, Peter M Keller, MD, Joachim Gnokoro, MD, Olivier Marcy, MD, Prof Marcel Yotebieng, MD, Lameck Diero, MD, Prof E Jane Carter, MD, Neesha Rockwood, PhD, Prof Robert J Wilkinson, PhD, Prof Helen Cox, PhD, Nicholas Ezati, MSc, Prof Alash’le G Abimiku, PhD, Jimena Collantes, MSc, Anchalee Avihingsanon, MD, Kamon Kawkitinarong, MD, Miriam Reinhard, Rico Hömke, Robin Huebner, PhD, Prof Sebastien Gagneux, PhD *, Prof Erik C Böttger, MD *, Prof Matthias Egger, MD  * on behalf of theInternational epidemiology Databases to Evaluate AIDS (IeDEA) consortium †

Published: February 07, 2019 / DOI:




Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory.


This multicentre cohort study was done in Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status.


We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9–42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5–94·2) and specificity 84·3% (80·3–87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70–19·95) for patients with discordant results potentially leading to under-treatment.


Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis.


National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.

Keywords: Mycobacterium tuberculosis; Antibiotics; Drugs Resistance.


Longitudinal #Outbreak of #MDR #Tuberculosis in a #Hospital Setting, #Serbia (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases, full page: (LINK). Abstract, edited.]

Volume 25, Number 3—March 2019 / Dispatch

Longitudinal Outbreak of Multidrug-Resistant Tuberculosis in a Hospital Setting, Serbia

Irena Arandjelović1  , Matthias Merker1, Elvira Richter, Thomas A. Kohl, Branislava Savić, Ivan Soldatović, Thierry Wirth, Dragana Vuković1, and Stefan Niemann1

Author affiliations: University of Belgrade, Belgrade, Serbia (I. Arandjelović, B. Savić, I. Soldatović, D. Vuković); Leibniz-Zentrum für Medizin und Biowissenschaften, Borstel, Germany (M. Merker, T.A. Kohl, S. Niemann); Laboratory Limbach, Heidelberg, Germany (E. Richter); Paris Sciences & Lettres University, Paris, France (T. Wirth); Sorbonne Universités, Paris (T. Wirth); German Center for Infection Research, Borstel, Germany (S. Niemann)



A retrospective population-based molecular epidemiologic study of multidrug-resistant Mycobacterium tuberculosis complex strains in Serbia (2008–2014) revealed an outbreak of TUR genotype strains in a psychiatric hospital starting around 1990. Drug unavailability, poor infection control, and schizophrenia likely fueled acquisition of additional resistance and bacterial fitness–related mutations over 2 decades.

Keywords: Antibiotics; Drugs Resistance; Mycobacterium tuberculosis; Nosocomial outbreaks; Serbia.


Cross-Border #Movement of Highly Drug- #Resistant #Mycobacterium tuberculosis from #Papua New Guinea to #Australia through Torres Strait Protected Zone, 2010–2015 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 3—March 2019 / Synopsis

Cross-Border Movement of Highly Drug-Resistant Mycobacterium tuberculosis from Papua New Guinea to Australia through Torres Strait Protected Zone, 2010–2015

Arnold Bainomugisa, Sushil Pandey, Ellen Donnan, Graham Simpson, J’Belle Foster, Evelyn Lavu, Stenard Hiasihri, Emma S. McBryde, Rendi Moke, Steven Vincent, Vitali Sintchenko, Ben J. Marais, Lachlan J.M. Coin, and Christopher Coulter

Author affiliations: Pathology Queensland, Brisbane, Queensland, Australia (A. Bainomugisa, S. Pandey, C. Coulter); The University of Queensland, Brisbane (A. Bainomugisa, L.J.M. Coin); Queensland Department of Health, Brisbane (E. Donnan, C. Coulter); Cairns Tuberculosis Unit, Cairns, Queensland, Australia (G. Simpson, S. Vincent); James Cook University, Townsville, Queensland, Australia (J. Foster, E.S. McBryde); Central Public Health Laboratory, Port Moresby, Papua New Guinea (E. Lavu); Western Province Health Office, Daru, Papua New Guinea (S. Hiasihri); Port Moresby General Hospital, Port Moresby (R. Moke); Westmead Hospital, Sydney, New South Wales, Australia (V. Sintchenko); The University of Sydney, Sydney (V. Sintchenko, B.J. Marais)



In this retrospective study, we used whole-genome sequencing (WGS) to delineate transmission dynamics, characterize drug-resistance markers, and identify risk factors of transmission among Papua New Guinea residents of the Torres Strait Protected Zone (TSPZ) who had tuberculosis diagnoses during 2010–2015. Of 117 isolates collected, we could acquire WGS data for 100; 79 were Beijing sublineage, which was associated with active transmission (odds ratio 6.190, 95% CI 2.221–18.077). Strains were distributed widely throughout the TSPZ. Clustering occurred more often within than between villages (p = 0.0013). Including 4 multidrug-resistant tuberculosis isolates from Australia citizens epidemiologically linked to the TSPZ into the transmission network analysis revealed 2 probable cross-border transmission events. All multidrug-resistant isolates (33/104) belonged to Beijing sublineage and had high-level isoniazid and ethionamide co-resistance; 2 isolates were extensively drug resistant. Including WGS in regional surveillance could improve tuberculosis transmission tracking and control strategies within the TSPZ.

Keywords: Mycobacterium tuberculosis; Antibiotics; Drugs resistance; Papua New Guinea; Australia.


#Synergy between circular #bacteriocin AS-48 and #ethambutol against #Mycobacterium tuberculosis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Synergy between circular bacteriocin AS-48 and ethambutol against Mycobacterium tuberculosis

Clara Aguilar-Pérez a,b#, Begoña Gracia a,b,c, Liliana Rodrigues a,b,c,d, Asunción Vitoria a,b,c,g, Rubén Cebrián e, Nathalie Deboosère f, Ok-ryul Song f, Priscille Brodin f, Mercedes Maqueda e and José A. Aínsa a,b,c#

Author Affiliations: a Departamento de Microbiología, Facultad de Medicina, and BIFI, Universidad de Zaragoza, Zaragoza, Spain; b Instituto de Investigación Sanitaria de Aragón (IIS-Aragón); {c} CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III; {d} Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID); {e} Departamento de Microbiología, Facultad de Ciencias, Universidad de Granada, Granada, Spain; f Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 8204 – CIIL – Center for Infection and Immunity of Lille, Lille, France; g Grupo de Estudio de Infecciones por Micobacterias (GEIM) de la SEIMC, Madrid, Spain



The increasing incidence of multi-drug resistant Mycobacterium tuberculosis and the very few drugs available for treatment is promoting the discovery and development of new molecules that could help in the control of this disease. Bacteriocin AS-48 is an antibacterial peptide produced by Enterococcus faecalis, active against several Gram-positive bacteria. We have found that AS-48 was active against Mycobacterium tuberculosis, including H37Rv and other reference and clinical strains, and also against some non-tuberculous clinical mycobacterial species. The combination of AS-48 with either lysozyme or with ethambutol (commonly used in the treatment of drug susceptible tuberculosis) increased the antituberculosis action of AS-48, showing a synergic interaction. Under these conditions, AS-48 exhibits a MIC close to some of the first-line antituberculosis agents. The inhibitory activity of AS-48 and its synergistic combination with ethambutol was also observed on M. tuberculosis infected macrophages.

Finally, AS-48 did not show any cytotoxicity against THP-1, MHS and J774.2 macrophage cell lines, at concentrations close to its MIC. In summary, bacteriocin AS-48 has an interesting antimycobacterial activity in vitro and low cytotoxicity, so further studies in vivo will contribute to its development as a potential additional drug for antituberculosis therapy.



#Corresponding authors: Clara Aguilar-Pérez, and José A. Aínsa, Microbiology Department, University of Zaragoza, C/Domingo Miral s/n 50009-Zaragoza, Spain.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Mycobacterium tuberculosis; Bacteriocins; Ethambutol.


#Verapamil targets membrane energetics in #Mycobacterium tuberculosis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Verapamil targets membrane energetics in Mycobacterium tuberculosis

Chao Chen1, Susana Gardete2, Robert Sander Jansen2,  Annanya Shetty3, Thomas Dick1,4, Kyu Y. Rhee2 and Véronique Dartois1,4*

Author Affiliations: 1 Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, United States; 2 Weill Cornell Medical College, Weill Department of Medicine, New York, New York USA 10065; 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 4 Department of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA



Mycobacterium tuberculosis (Mtb) kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several anti-tuberculosis (TB) drugs in vitro and in vivo. This potentiation is widely attributed to inhibition of Mtb’s efflux pumps, resulting in intrabacterial drug accumulation. Here, we confirm and quantify verapamil’s synergy with several anti-TB drugs, including bedaquiline and clofazimine, but find that this effect is not due to increased intrabacterial drug accumulation. Consistent with its in vitro potentiating effects on TB drugs that target or require oxidative phosphorylation, we show that the cationic amphiphile verapamil disrupts membrane function and induces a membrane stress response, similar to other membrane-active agents. We recapitulate these activities in vitro using inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. Consistent with such mechanism of action, we observe bactericidal activity against non-replicating ‘persister’ Mtb. In addition, we demonstrate a pharmacokinetic interaction whereby human-equivalent doses of verapamil cause a boost of rifampicin exposure in mice, providing a potential explanation for the observed treatment shortening effect of verapamil in mice receiving first line drugs. Our findings thus elucidate the mechanistic basis for verapamil’s potentiation of TB drugs in vitro and in vivo, and highlight a previously unrecognized role for Mtb’s membrane as pharmacologic target.



*Correspondence to:

Copyright © 2018 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; M. Tuberculosis; Verapamil.