Tuberculosis: a balanced diet of lipids and carbohydrates

2008 ◽  
Vol 36 (4) ◽  
pp. 555-565 ◽  
Author(s):  
Veemal Bhowruth ◽  
Luke J. Alderwick ◽  
Alistair K. Brown ◽  
Apoorva Bhatt ◽  
Gurdyal S. Besra
Keyword(s):  
Drug Targets ◽  
Infectious Agent ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Macromolecular Structure ◽  
New Era ◽  
Balanced Diet ◽  
Site Of Action ◽  
Wall Components

In spite of effective antibiotics to treat TB (tuberculosis) since the early 1960s, we enter the new millennium with TB currently the leading cause of death from a single infectious agent, killing more than 3 million people worldwide each year. Thus an understanding of drug-resistance mechanisms, the immunobiology of cell wall components to elucidate host–pathogen interactions and the discovery of new drug targets are now required for the treatment of TB. Above the plasma membrane is a classical chemotype IV peptidoglycan to which is attached the macromolecular structure, mycolyl-arabinogalactan via a unique diglycosylphosphoryl bridge. The present review discusses the assembly of the mAGP (mycolyl-arabinogalactan–peptidoglycan) complex and the site of action of EMB (ethambutol), bringing forward a new era in TB research and focus for new drugs to combat multidrug-resistant TB.

Structure, function and biosynthesis of the Mycobacterium tuberculosis cell wall: arabinogalactan and lipoarabinomannan assembly with a view to discovering new drug targets

2007 ◽  
Vol 35 (5) ◽  
pp. 1325-1328 ◽  
Author(s):  
L.J. Alderwick ◽  
H.L. Birch ◽  
A.K. Mishra ◽  
L. Eggeling ◽  
G.S. Besra
Keyword(s):  
Cell Wall ◽  
Drug Targets ◽  
Infectious Agent ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
New Era ◽  
New Drug ◽  
Site Of Action ◽  
Wall Components

In spite of effective antibiotics to treat TB (tuberculosis) since the early 1960s, we enter the new millennium with TB, currently the leading cause of death from a single infectious agent, killing more than three million people worldwide each year. Thus an understanding of drug-resistance mechanisms, the immunobiology of cell wall components to elucidate host–pathogen interactions and the discovery of new drug targets are now required for the treatment of TB. Above the plasma membrane is a classical chemotype IV PG (peptidoglycan) to which is attached the macromolecular structure, mycolyl-arabinogalactan, via a unique diglycosylphosphoryl bridge. This review will discuss the assembly of the mAGP (mycolyl-arabinogalactan-peptidoglycan), its associated glycolipids and the site of action of EMB (ethambutol), bringing forward a new era in TB research and focus on new drugs to combat multidrug resistant TB.

scholarly journals Solution Structures and Dynamic Assembly of the 24-Meric Plasmodial Pdx1–Pdx2 Complex

2020 ◽  
Vol 21 (17) ◽  
pp. 5971
Author(s):  
Najeeb Ullah ◽  
Hina Andaleeb ◽  
Celestin Nzanzu Mudogo ◽  
Sven Falke ◽  
Christian Betzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Pyridoxal Phosphate ◽  
Plasmodium Species ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Enzyme Complex ◽  
Solution Structures ◽  
Dynamic Assembly ◽  
Bioanalytical Techniques ◽  
Initial Drug

Plasmodium species are protozoan parasites causing the deadly malaria disease. They have developed effective resistance mechanisms against most antimalarial medication, causing an urgent need to identify new antimalarial drug targets. Ideally, new drugs would be generated to specifically target the parasite with minimal or no toxicity to humans, requiring these drug targets to be distinctly different from the host’s metabolic processes or even absent in the host. In this context, the essential presence of vitamin B6 biosynthesis enzymes in Plasmodium, the pyridoxal phosphate (PLP) biosynthesis enzyme complex, and its absence in humans is recognized as a potential drug target. To characterize the PLP enzyme complex in terms of initial drug discovery investigations, we performed structural analysis of the Plasmodium vivax PLP synthase domain (Pdx1), glutaminase domain (Pdx2), and Pdx1–Pdx2 (Pdx) complex (PLP synthase complex) by utilizing complementary bioanalytical techniques, such as dynamic light scattering (DLS), X-ray solution scattering (SAXS), and electron microscopy (EM). Our investigations revealed a dodecameric Pdx1 and a monodispersed Pdx complex. Pdx2 was identified in monomeric and in different oligomeric states in solution. Interestingly, mixing oligomeric and polydisperse Pdx2 with dodecameric monodisperse Pdx1 resulted in a monodispersed Pdx complex. SAXS measurements revealed the low-resolution dodecameric structure of Pdx1, different oligomeric structures for Pdx2, and a ring-shaped dodecameric Pdx1 decorated with Pdx2, forming a heteromeric 24-meric Pdx complex.

scholarly journals Activity of Semi-Synthetic Mulinanes against MDR, Pre-XDR, and XDR Strains of Mycobacterium tuberculosis

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 876
Author(s):  
María Alejandrina Martínez-González ◽  
Luis Manuel Peña-Rodríguez ◽  
Andrés Humberto Uc-Cachón ◽  
Jorge Bórquez ◽  
Mario J. Simirgiotis ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Infectious Agent ◽  
Vero Cells ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Adjuvant Effect ◽  
Extensively Drug Resistant

Tuberculosis causes more than 1.2 million deaths each year. Worldwide, it is the first cause of death by a single infectious agent. The emergence of drug-resistant strains has limited pharmacological treatment of the disease and today, new drugs are urgently needed. Semi-synthetic mulinanes have previously shown important activity against multidrug-resistant (MDR) Mycobacterium tuberculosis. In this investigation, a new set of semi-synthetic mulinanes were synthetized, characterized, and evaluated for their in vitro activity against three drug-resistant clinical isolates of M. tuberculosis: MDR, pre-extensively Drug-Resistant (pre-XDR), and extensively Drug-Resistant (XDR), and against the drug-susceptible laboratory reference strain H37Rv. Derivative 1a showed the best anti-TB activity (minimum inhibitory concentration [MIC] = 5.4 µM) against the susceptible strain and was twice as potent (MIC = 2.7 µM) on the MDR, pre-XDR, and XDR strains and also possessed a bactericidal effect. Derivative 1a was also tested for its anti-TB activity in mice infected with the MDR strain. In this case, 1a produced a significant reduction of pulmonary bacilli loads, six times lower than the control, when tested at 0.2536 mg/Kg. In addition, 1a demonstrated an adjuvant effect by shortening second-line chemotherapy. Finally, the selectivity index of >15.64 shown by 1a when tested on Vero cells makes this derivative an important candidate for future studies in the development of novel antitubercular agents.

scholarly journals Targeting the bacterial SOS response for new antimicrobial agents: drug targets, molecular mechanisms and inhibitors

2021 ◽  
Author(s):  
Thomas Lanyon-Hogg
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Structure And Function ◽  
Drug Resistant ◽  
Target Validation ◽  
Sos Pathway ◽  
And Function

Antimicrobial resistance is a pressing threat to global health, with multidrug-resistant pathogens becoming increasingly prevalent. The bacterial SOS pathway functions in response to DNA damage that occurs during infection, initiating several pro-survival and resistance mechanisms, such as DNA repair and hypermutation. This makes SOS pathway components potential targets that may combat drug-resistant pathogens and decrease resistance emergence. This review discusses the mechanism of the SOS pathway; the structure and function of potential targets AddAB, RecBCD, RecA and LexA; and efforts to develop selective small-molecule inhibitors of these proteins. These inhibitors may serve as valuable tools for target validation and provide the foundations for desperately needed novel antibacterial therapeutics.

scholarly journals High-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes

Parasitology ◽  
2013 ◽  
Vol 141 (1) ◽  
pp. 77-82 ◽  
Author(s):  
DAVID HORN
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Drug Targets ◽  
Sequence Data ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Uptake ◽  
Microbial Pathogens ◽  
African Trypanosomes ◽  
Genome Scale

SUMMARYThe availability of genome sequence data has facilitated the development of high-throughput genetic screening approaches in microbial pathogens. In the African trypanosome, Trypanosoma brucei, genome-scale RNA interference screens have proven particularly effective in this regard. These genetic screens allow for identification of the genes that contribute to a particular pathway or mechanisms of interest. The approach has been used to assess loss-of-fitness, revealing the genes and proteins required for parasite viability and growth. The outputs from these screens predict essential and dispensable genes and facilitate drug target prioritization efforts. The approach has also been used to assess resistance to anti-trypanosomal drugs, revealing the genes and proteins that facilitate drug uptake and action. These outputs also highlight likely mechanisms underlying clinically relevant drug resistance. I first review these findings in the context of what we know about current drugs. I then describe potential contributions that these high-throughput approaches could make to the development and implementation of new drugs.

scholarly journals Acinetobacter baumanniiOxyR Regulates the Transcriptional Response to Hydrogen Peroxide

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Lillian J. Juttukonda ◽  
Erin R. Green ◽  
Zachery R. Lonergan ◽  
Marie C. Heffern ◽  
Christopher J. Chang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Drug Targets ◽  
Transcriptional Response ◽  
Transcriptional Regulator ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
World Health ◽  
Content Type

ABSTRACTAcinetobacter baumanniiis a Gram-negative opportunistic pathogen that causes diverse infections, including pneumonia, bacteremia, and wound infections. Due to multiple intrinsic and acquired antimicrobial-resistance mechanisms,A. baumanniiisolates are commonly multidrug resistant, and infections are notoriously difficult to treat. The World Health Organization recently highlighted carbapenem-resistantA. baumanniias a “critical priority” for the development of new antimicrobials because of the risk to human health posed by this organism. Therefore, it is important to discover the mechanisms used byA. baumanniito survive stresses encountered during infection in order to identify new drug targets. In this study, by use ofin vivoimaging, we identified hydrogen peroxide (H2O2) as a stressor produced in the lung duringA. baumanniiinfection and defined OxyR as a transcriptional regulator of the H2O2stress response. Upon exposure to H2O2,A. baumanniidifferentially transcribes several hundred genes. However, the transcriptional upregulation of genes predicted to detoxify hydrogen peroxide is abolished in anA. baumanniistrain in which the transcriptional regulatoroxyRis genetically inactivated. Moreover, inactivation ofoxyRin both antimicrobial-susceptible and multidrug-resistantA. baumanniistrains impairs growth in the presence of H2O2. OxyR is a direct regulator ofkatEandahpF1, which encode the major H2O2-degrading enzymes inA. baumannii, as confirmed through measurement of promoter binding by recombinant OxyR in electromobility shift assays. Finally, anoxyRmutant is less fit than wild-typeA. baumanniiduring infection of the murine lung. This work reveals a mechanism used by this important human pathogen to survive H2O2stress encountered during infection.

Molecular mechanisms associated with quinolone resistance in Enterobacteriaceae: review and update

2020 ◽  
Vol 114 (10) ◽  
pp. 770-781 ◽  
Author(s):  
Robab Azargun ◽  
Pourya Gholizadeh ◽  
Vahid Sadeghi ◽  
Hasan Hosainzadegan ◽  
Vahideh Tarhriz ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Drug Binding ◽  
Quinolone Resistance ◽  
New Drugs ◽  
Bacterial Strains ◽  
Active Efflux

Abstract Background Quinolones are broad-spectrum antibiotics, which are used for the treatment of different infectious diseases associated with Enterobacteriaceae. During recent decades, the wide use as well as overuse of quinolones against diverse infections has led to the emergence of quinolone-resistant bacterial strains. Herein, we present the development of quinolone antibiotics, their function and also the different quinolone resistance mechanisms in Enterobacteriaceae by reviewing recent literature. Methods All data were extracted from Google Scholar search engine and PubMed site, using keywords; quinolone resistance, Enterobacteriaceae, plasmid-mediated quinolone resistance, etc. Results and conclusion The acquisition of resistance to quinolones is a complex and multifactorial process. The main resistance mechanisms consist of one or a combination of target-site gene mutations altering the drug-binding affinity of target enzymes. Other mechanisms of quinolone resistance are overexpression of AcrAB-tolC multidrug-resistant efflux pumps and downexpression of porins as well as plasmid-encoded resistance proteins including Qnr protection proteins, aminoglycoside acetyltransferase (AAC(6′)-Ib-cr) and plasmid-encoded active efflux pumps such as OqxAB and QepA. The elucidation of resistance mechanisms will help researchers to explore new drugs against the resistant strains.

scholarly journals Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi

2021 ◽  
Vol 14 (5) ◽  
pp. 488
Author(s):  
Lucie Peyclit ◽  
Hanane Yousfi ◽  
Jean-Marc Rolain ◽  
Fadi Bittar
Keyword(s):  
Opportunistic Infections ◽  
Fungal Infections ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Medical Community ◽  
Medical Mycology ◽  
Candida Auris

Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal drugs as azoles and polyenes can lead to clinical failure, particularly in immunocompromised individuals. Difficulties related to treating fungal infections combined with the time required to develop new drugs, require urgent consideration of other therapeutic alternatives. Drug repurposing is one of the most promising and rapid solutions that the scientific and medical community can turn to, with low costs and safety advantages. To treat life-threatening resistant fungal infections, drug repurposing has led to the consideration of well-known and potential molecules as a last-line therapy. The aim of this review is to provide a summary of current antifungal compounds and their main resistance mechanisms, following by an overview of the antifungal activity of non-traditional antimicrobial drugs. We provide their eventual mechanisms of action and the synergistic combinations that improve the activity of current antifungal treatments. Finally, we discuss drug repurposing for the main emerging multidrug resistant (MDR) fungus, including the Candida auris, Aspergillus or Cryptococcus species.

scholarly journals Bacterial Resistance to Antimicrobial Agents

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 593
Author(s):  
Manuel F. Varela ◽  
Jerusha Stephen ◽  
Manjusha Lekshmi ◽  
Manisha Ojha ◽  
Nicholas Wenzel ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Drug Targets ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Health Sector ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Cellular Mechanisms ◽  
Causative Agents

Bacterial pathogens as causative agents of infection constitute an alarming concern in the public health sector. In particular, bacteria with resistance to multiple antimicrobial agents can confound chemotherapeutic efficacy towards infectious diseases. Multidrug-resistant bacteria harbor various molecular and cellular mechanisms for antimicrobial resistance. These antimicrobial resistance mechanisms include active antimicrobial efflux, reduced drug entry into cells of pathogens, enzymatic metabolism of antimicrobial agents to inactive products, biofilm formation, altered drug targets, and protection of antimicrobial targets. These microbial systems represent suitable focuses for investigation to establish the means for their circumvention and to reestablish therapeutic effectiveness. This review briefly summarizes the various antimicrobial resistance mechanisms that are harbored within infectious bacteria.

Delamanid Resistance: Update and Clinical Management

2020 ◽  
Author(s):  
Thi Van Anh Nguyen ◽  
Richard M Anthony ◽  
Thi Thu Huyen Cao ◽  
Anne-Laure Bañuls ◽  
Van Anh Thi Nguyen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Drug Susceptibility Testing ◽  
New Drugs ◽  
Rapid Acquisition ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

Abstract Delamanid, a-first-in-class bicyclic nitroimidazole, was recently approved for multidrug-resistant tuberculosis treatment. Pitted against the hope for improving treatment outcomes is the threat of the rapid resistance emergence. This review provides information on the mechanisms of action, resistance emergence, and drug susceptibility testing (DST) for delamanid. Delamanid resistance has already been reported in both in vitro experiments and clinical settings. Although mutations conferring delamanid resistance have been identified in fbiA, fbiB, fbiC, ddn, and fgd1 genes of Mycobacterium tuberculosis, knowledge about the molecular resistance mechanisms is limited, and there remains no standardized DST method. The rapid acquisition of delamanid resistance emphasizes the need for optimal use of new drugs, the need for drug resistance surveillance, and a comprehensive understanding of drug resistance mechanisms. Further studies are necessary to investigate genetic and phenotypic changes that determine clinically relevant delamanid resistance to help develop a rapid delamanid DST.

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