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Antibiotics
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Antibiotics against Tuberculosis
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Antibiotics against Tuberculosis

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 36644

Special Issue Editor

Dr. Juan Manuel Belardinelli

E-Mail Website
Guest Editor
Department of Microbiology, Immunology & Pathology, Colorado State University, Fort Collins, CO 0523-1682, USA
Interests: Mycobacterium tuberculosis; NTMs; drug discovery; antimicrobial resistance; mechanism of action; cell wall synthesis; membrane transport; lipid synthesis; mycolic acids; MmpLs

Special Issue Information

Dear Colleagues,

Tuberculosis remains the major cause of death worldwide by an infectious agent. According to the World Health Organization, 1.5 million people died from tuberculosis in 2018. Furthermore, the increase in multidrug-resistant (MDR-TB) and extremely drug-resistant (XDR-TB) cases is alarming and continues to constitute a public health crisis. Despite the advances that have taken place in the last years, with the inclusion of much needed new antibiotics, considerable progress must still be made in order to tackle this deadly disease. We urgently need new antibiotics with better efficacy, fewer side effects, and preferably the ability to shorten treatment. In this Special Issue of Antibiotics, we will cover the latest advances in the research of drugs to fight Mycobacterium tuberculosis. Thus, this Special Issue will be covering but not limited to: Drug discovery, drug screening, synthesis/isolation/repurposing of antimicrobials, antimicrobial resistance, mechanism of action, and new drug regimens/combinations. We especially encourage the submission of original articles and reviews.

Dr. Juan Manuel Belardinelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Mycobacterium tuberculosis
  • Drug Development
  • Antimicrobial resistance
  • Antimicrobial action
  • Drug Screening/Synthesis
  • Tuberculosis treatment
  • MDR
  • XDR

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Published Papers (5 papers)

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Research

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7 pages, 388 KiB  
Article
Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
by Dinah Binte Aziz, Mei Lin Go and Thomas Dick
Antibiotics 2020, 9(2), 72; https://doi.org/10.3390/antibiotics9020072 - 10 Feb 2020
Cited by 24 | Viewed by 4632
Abstract
Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by Mycobacterium abscessus (Mab). However, many strains harbor the CLR-inducible CLR resistance gene erm41, encoding a ribosome methylase. Induction of erm41 is mediated by the transcription factor [...] Read more.
Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by Mycobacterium abscessus (Mab). However, many strains harbor the CLR-inducible CLR resistance gene erm41, encoding a ribosome methylase. Induction of erm41 is mediated by the transcription factor whiB7. We hypothesized that an inhibitor of RNA synthesis should be able to block the whiB7–erm41 induction response to CLR exposure and thus suppress CLR resistance. Recently, we discovered that the rifampicin analog rifabutin (RFB) shows attractive potency against Mab. To determine whether RFB-CLR combinations are synergistic, a checkerboard analysis against a collection of erm41 positive and negative Mab strains was carried out. This revealed synergy of the two drugs for erm41 positive but not for erm41 negative strains. To determine whether RFB’s potentiation effect was due to inhibition of the transcriptional induction of the whiB7–erm41 resistance system, we measured the effect of CLR alone and in combination with RFB on whiB7 and erm41 mRNA levels. CLR alone strongly induced whiB7 and erm41 expression as expected. The synergistic, growth-inhibiting combination of RFB with CLR blocked induction of both genes. These results suggest that RFB suppresses inducible CLR resistance by preventing induction of whiB7 and erm41 expression. Full article
(This article belongs to the Special Issue Antibiotics against Tuberculosis)
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Review

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14 pages, 1278 KiB  
Review
Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid
by Luisa Maria Nieto Ramirez, Karina Quintero Vargas and Gustavo Diaz
Antibiotics 2020, 9(3), 133; https://doi.org/10.3390/antibiotics9030133 - 23 Mar 2020
Cited by 37 | Viewed by 6917
Abstract
Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR [...] Read more.
Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after their introduction in clinical practice. Early detection of resistant strains to BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we present a systematic review aiming to define all available genotypic variants linked to different levels of resistance to BDQ and DLM that have been described through whole genomic sequencing (WGS) and the available drug susceptibility testing methods. During the review, we performed a thorough analysis of 18 articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE, while mutations in pepQ were linked to a low-level of resistance for BDQ. For DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in phenotypically resistant cases, while all the mutations in fbiB were reported only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection of heteroresistance to both drugs. In conclusion, we present a comprehensive panel of gene mutations linked to different levels of drug resistance to BDQ and DLM. Full article
(This article belongs to the Special Issue Antibiotics against Tuberculosis)
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19 pages, 972 KiB  
Review
Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation
by Sultan Ahmed, Rubhana Raqib, Guðmundur Hrafn Guðmundsson, Peter Bergman, Birgitta Agerberth and Rokeya Sultana Rekha
Antibiotics 2020, 9(1), 21; https://doi.org/10.3390/antibiotics9010021 - 7 Jan 2020
Cited by 30 | Viewed by 10153
Abstract
Tuberculosis (TB) is one of the leading causes of mortality and morbidity, particularly in developing countries, presenting a major threat to the public health. The currently recommended long term treatment regimen with multiple antibiotics is associated with poor patient compliance, which in turn, [...] Read more.
Tuberculosis (TB) is one of the leading causes of mortality and morbidity, particularly in developing countries, presenting a major threat to the public health. The currently recommended long term treatment regimen with multiple antibiotics is associated with poor patient compliance, which in turn, may contribute to the emergence of multi-drug resistant TB (MDR-TB). The low global treatment efficacy of MDR-TB has highlighted the necessity to develop novel treatment options. Host-directed therapy (HDT) together with current standard anti-TB treatments, has gained considerable interest, as HDT targets novel host immune mechanisms. These immune mechanisms would otherwise bypass the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (Mtb), which may be mutated to cause antibiotic resistance. Additionally, host-directed therapies against TB have been shown to be associated with reduced lung pathology and improved disease outcome, most likely via the modulation of host immune responses. This review will provide an update of host-directed therapies and their mechanism(s) of action against Mycobacterium tuberculosis. Full article
(This article belongs to the Special Issue Antibiotics against Tuberculosis)
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25 pages, 11392 KiB  
Review
Biosynthesis of Galactan in Mycobacterium tuberculosis as a Viable TB Drug Target?
by Zuzana Konyariková, Karin Savková, Stanislav Kozmon and Katarína Mikušová
Antibiotics 2020, 9(1), 20; https://doi.org/10.3390/antibiotics9010020 - 6 Jan 2020
Cited by 18 | Viewed by 6197
Abstract
While target-based drug design has proved successful in several therapeutic areas, this approach has not yet provided compelling outcomes in the field of antibacterial agents. This statement remains especially true for the development of novel therapeutic interventions against tuberculosis, an infectious disease that [...] Read more.
While target-based drug design has proved successful in several therapeutic areas, this approach has not yet provided compelling outcomes in the field of antibacterial agents. This statement remains especially true for the development of novel therapeutic interventions against tuberculosis, an infectious disease that is among the top ten leading causes of death globally. Mycobacterial galactan is an important component of the protective cell wall core of the tuberculosis pathogen and it could provide a promising target for the design of new drugs. In this review, we summarize the current knowledge on galactan biosynthesis in Mycobacterium tuberculosis, including landmark findings that led to the discovery and understanding of three key enzymes in this pathway: UDP-galactose mutase, and galactofuranosyl transferases GlfT1 and GlfT2. Moreover, we recapitulate the efforts aimed at their inhibition. The predicted common transition states of the three enzymes provide the lucrative possibility of multitargeting in pharmaceutical development, a favourable property in the mitigation of drug resistance. We believe that a tight interplay between target-based computational approaches and experimental methods will result in the development of original inhibitors that could serve as the basis of a new generation of drugs against tuberculosis. Full article
(This article belongs to the Special Issue Antibiotics against Tuberculosis)
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12 pages, 911 KiB  
Review
Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline
by Jickky Palmae Sarathy, Gerhard Gruber and Thomas Dick
Antibiotics 2019, 8(4), 261; https://doi.org/10.3390/antibiotics8040261 - 11 Dec 2019
Cited by 46 | Viewed by 7894
Abstract
Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme’s c-ring to block its rotation, thus inhibiting ATP synthesis [...] Read more.
Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme’s c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme’s catalytic α3β3-headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme’s ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α3β3-headpiece. However, this mechanism is controversial as the drug’s binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ’s mechanisms of action. In this review, we first summarize discoveries on BDQ’s mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ’s anti-mycobacterial activity. Full article
(This article belongs to the Special Issue Antibiotics against Tuberculosis)
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