Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.

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Intracellular Drug Targets In Mycobacterium Tuberculosis Revealed By A Chemo-Genetic Approach

10.21203/rs.3.rs-946186/v1 ◽

2021 ◽

Author(s):

Clement K.M. Tsui ◽

Flavia Sorrentino ◽

Narula Gagandeep ◽

Alfonso Mendoza Losanna ◽

Ruben Gonzalez Rio ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Resistance Mechanisms ◽

Sequencing Analysis ◽

Chronic Lung Diseases ◽

Candidate Drug ◽

A Genome ◽

Novel Drug

Abstract Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. It causes chronic lung diseases to one third of the world’s population. Chemo-genetic characterization through in vitro evolution combined with whole genome sequencing analysis can identify novel drug targets and drug resistance genes in Mtb. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3, ethA, mbtA, we discovered several unrecognized candidate drug targets including prrB and TB18.5. The exploration of the M. tuberculosis chemical mutant genomes could help novel drug discovery and structural biology of compounds and asscoiated mechanisms of action relevant to tuberculosis treatment.

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Genotypic analysis of multidrug-resistant Mycobacterium tuberculosis isolates from Monterrey, Mexico

Journal of Medical Microbiology ◽

10.1099/jmm.0.05343-0 ◽

2004 ◽

Vol 53 (2) ◽

pp. 107-113 ◽

Cited By ~ 58

Author(s):

Srinivas V. Ramaswamy ◽

Shu-Jun Dou ◽

Adrian Rendon ◽

Zhenhua Yang ◽

M. Donald Cave ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Secondary Resistance ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Genotypic Analysis ◽

Mdr Tb

Thirty-seven multidrug-resistant and 13 pan-susceptible isolates of Mycobacterium tuberculosis were analysed for the diversity of genotypes associated with known drug-resistance mechanisms. The isolates were obtained from patients attending a university tuberculosis clinic in Monterrey, Mexico. A total of 25 IS6110-RFLP patterns were obtained from the multidrug-resistant tuberculosis (MDR-TB) isolates. Approximately 65 % of the MDR-TB isolates were attributed to secondary resistance. Different drug-susceptibility patterns were seen with the clustered isolates. The percentage of isolates resistant to isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STR) was 100, 97.3, 48.7 and 67.6, respectively. The most common resistance-associated polymorphisms for the four drugs were as follows: INH, Ser315Thr (67.6 %) in katG; RIF, Ser450Leu (41.7 %) in rpoB; EMB, Met306Ile/Val/Leu (66.7 %) in embB; and STR, Lys43Arg (24 %) in rpsL. Drug-resistance-associated mutations were similar to changes occurring in isolates from other areas of the world, but unique, previously unreported, mutations in katG (n = 5), rpoB (n = 1) and rrs (n = 3) were also identified.

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