scholarly journals Antibiotic binding releases autoinhibition of the TipA multidrug-resistance transcriptional regulator

2020 ◽  
Vol 295 (51) ◽  
pp. 17865-17876
Author(s):  
Xuguang Jiang ◽  
Linjuan Zhang ◽  
Maikun Teng ◽  
Xu Li
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Bacterial Resistance ◽  
Caulobacter Crescentus ◽  
Antimicrobial Drugs ◽  
Promoter Dna ◽  
Biochemical Analyses ◽  
Apo State

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.

scholarly journals Antibiotic Resistance Patterns in a University Hospital in Al-Kharj City

2019 ◽  
pp. 1-5
Author(s):  
Nehad J. Ahmed ◽  
Mohd F. Khan
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Resistance ◽  
Treatment Guidelines ◽  
Resistance Rate ◽  
University Hospital ◽  
Antimicrobial Drugs ◽  
E Coli ◽  
Resistance Patterns ◽  
Antibiotic Resistance Patterns

Introduction: Antibiotics are medications that are used to kill a bacterium which causes different infections. The misuse of these medications has contributed to the development of bacterial resistance. In order to predict the efficacy of the antimicrobial drugs and to guide antimicrobial therapy, antibiogram should be used. Objective: This study aims to explore the Antibiotic resistance patterns in a university hospital in AL-kharj city. Methods: Data from a university hospital in Al-Kharj city were used to assess the in vitro antimicrobial susceptibility rates for different types of bacteria. We included all bacterial and fungal cultures in the last 2 years. Results: The most common bacterium was E. coli and the most common fungus pathogen was Candida albicans. There was a low resistance rate to gentamicin, imipenem, meropenem and amikacin for the studied bacteria pathogens and high resistance rate for some antibiotics such as erythromycin, tetracycline and ampicillin. Conclusion: The physicians should follow the treatment guidelines and they should know the susceptibility rate of different bacteria to prescribe antibiotics appropriately.

scholarly journals Structure of the unique tetrameric STENOFOLIA homeodomain bound with target promoter DNA

2021 ◽  
Vol 77 (8) ◽  
Author(s):  
Prabhat Kumar Pathak ◽  
Fei Zhang ◽  
Shuxia Peng ◽  
Lifang Niu ◽  
Juhi Chaturvedi ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Hydrophobic Surface ◽  
Promoter Sequence ◽  
In Planta ◽  
Embryo Patterning ◽  
Stem Cell Maintenance ◽  
C Terminus ◽  
Promoter Dna

Homeobox transcription factors are key regulators of morphogenesis and development in both animals and plants. In plants, the WUSCHEL-related homeobox (WOX) family of transcription factors function as central organizers of several developmental programs ranging from embryo patterning to meristematic stem-cell maintenance through transcriptional activation and repression mechanisms. The Medicago truncatula STENOFOLIA (STF) gene is a master regulator of leaf-blade lateral development. Here, the crystal structure of the homeodomain (HD) of STF (STF-HD) in complex with its promoter DNA is reported at 2.1 Å resolution. STF-HD binds DNA as a tetramer, enclosing nearly the entire bound DNA surface. The STF-HD tetramer is partially stabilized by docking of the C-terminal tail of one protomer onto a conserved hydrophobic surface on the head of another protomer in a head-to-tail manner. STF-HD specifically binds TGA motifs, although the promoter sequence also contains TAAT motifs. Helix α3 not only serves a canonical role as a base reader in the major groove, but also provides DNA binding in the minor groove through basic residues located at its C-terminus. The structural and functional data in planta reported here provide new insights into the DNA-binding mechanisms of plant-specific HDs from the WOX family of transcription factors.

scholarly journals Bacterial Resistance in Ophthalmology – Resistance Profile, Influencing Factors and Prevention Methods. A Review

2021 ◽  
Vol 28 (2) ◽  
pp. 127-137
Author(s):  
Matei POPA-CHERECHEANU ◽  
◽  
Alina POPA-CHERECHEANU ◽  
Dan George DELEANU ◽  
Mihai Aurelian GHITA ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Antimicrobial Resistance ◽  
Influencing Factors ◽  
Bacterial Resistance ◽  
Topical Antibiotics ◽  
Resistance Profile ◽  
Ocular Infections ◽  
Prevention Methods ◽  
New Treatments

Ocular infections vary greatly in severity. Studies have tried to identify certain patterns related to the ocular microbiome in the studied populations in order to identify risk populations, new treatments and prophylaxis guidelines. However, it is critical to determine which antibiotics should be used in various situations and where alternatives to antibiotics are appropriate. Results of many studies show that high levels of antibiotic resistance in ophthalmology and multidrug resistance continue to be a reality and a challenge today. Iodine-povidone and chlorhexidine are two major antiseptics used in ophthalmology. It is hoped that future reports show good results without the use of antibiotics will encourage ophthalmologists to limit the use of topical antibiotics, reducing the rate of antimicrobial resistance.

scholarly journals Alteration of Transcriptional Regulator Rob In Vivo: Enhancement of Promoter DNA Binding and Antibiotic Resistance in the Presence of Nucleobase Amino Acids

Biochemistry ◽  
2020 ◽  
Vol 59 (12) ◽  
pp. 1217-1220 ◽  
Author(s):  
Chao Zhang ◽  
Shengxi Chen ◽  
Xiaoguang Bai ◽  
Larisa M. Dedkova ◽  
Sidney M. Hecht
Keyword(s):  
Amino Acids ◽  
Antibiotic Resistance ◽  
Dna Binding ◽  
Transcriptional Regulator ◽  
Promoter Dna

scholarly journals The bacterial multidrug resistance regulator BmrR distorts promoter DNA to activate transcription

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chengli Fang ◽  
Linyu Li ◽  
Yihan Zhao ◽  
Xiaoxian Wu ◽  
Steven J. Philips ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Multidrug Resistance ◽  
Rna Polymerase ◽  
Transcriptional Activation ◽  
Promoter Activity ◽  
Transcription Activation ◽  
Core Enzyme ◽  
Upstream Promoter ◽  
Promoter Dna

AbstractThe MerR-family proteins represent a unique family of bacteria transcription factors (TFs), which activate transcription in a manner distinct from canonical ones. Here, we report a cryo-EM structure of a B. subtilis transcription activation complex comprising B. subtilis six-subunit (2αββ‘ωε) RNA Polymerase (RNAP) core enzyme, σA, a promoter DNA, and the ligand-bound B. subtilis BmrR, a prototype of MerR-family TFs. The structure reveals that RNAP and BmrR recognize the upstream promoter DNA from opposite faces and induce four significant kinks from the −35 element to the −10 element of the promoter DNA in a cooperative manner, which restores otherwise inactive promoter activity by shortening the length of promoter non-optimal −35/−10 spacer. Our structure supports a DNA-distortion and RNAP-non-contact paradigm of transcriptional activation by MerR TFs.

scholarly journals Application of antibiotics in agriculture and alternatives of their use

2021 ◽  
pp. 65-70
Author(s):  
Maria Sergeevna Miroshnikova ◽  
Elena Petrovna Miroshnikova ◽  
Azamat Ersainovich Arinzhanov ◽  
Yuliya Vladimirovna Kilyakova
Keyword(s):  
Antibiotic Resistance ◽  
Environmental Samples ◽  
Bacterial Resistance ◽  
Animal Husbandry ◽  
Agricultural Practice ◽  
Antimicrobial Drugs ◽  
The World ◽  
Food And Feed ◽  
Made In

The use of antibiotics in medicine, plant growing and animal husbandry has led to the spread of bacterial resistance to antimicrobial drugs. Tetracyclines are a chemical group of great importance due to the widespread use of these preparations  in agriculture. Due to the fact that significant quantities of tetracycline antimicrobial drugs are used all over the world, their monitoring plays an important role. Therefore, progress needs to be made in antibiotic analysis to assess the correct use and dosage of tetracyclines in food and feed, as well as possible residues in relevant environmental samples. The review presents an analysis of the data of modern studies aimed at studying the problem of antibiotic resistance caused by antimicrobial preparations  of the tetracyclines group in world agricultural practice. Data on existing and potential alternatives to antibiotics in animal husbandry are presented.

scholarly journals Dueling Regulatory Properties of a Transcriptional Activator (MtrA) and Repressor (MtrR) That Control Efflux Pump Gene Expression in Neisseria gonorrhoeae

mBio ◽  
2012 ◽  
Vol 3 (6) ◽  
Author(s):  
Yaramah M. Zalucki ◽  
Vijaya Dhulipala ◽  
William M. Shafer
Keyword(s):  
Antibiotic Resistance ◽  
Dna Binding ◽  
Neisseria Gonorrhoeae ◽  
Binding Site ◽  
Transcriptional Activation ◽  
Efflux Pump ◽  
Transcriptional Repressor ◽  
Transcriptional Activator ◽  
Multidrug Efflux Pump ◽  
Content Type

ABSTRACTMtrA is a member of the AraC family of transcriptional regulators and has been shown to play an important role in enhancing transcription of themtrCDEoperon, which encodes a tripartite multidrug efflux pump, when gonococci are exposed to a sublethal level of antimicrobials. Heretofore, the DNA-binding properties of MtrA were unknown. In order to understand how MtrA activatesmtrCDEexpression, we successfully purified MtrA and found that it could bind specifically to themtrCDEpromoter region. The affinity of MtrA for themtrCDEpromoter increased 2-fold in the presence of a known effector and substrate of the MtrCDE pump, the nonionic detergent Triton X-100 (TX-100). When placed in competition with MtrR, the transcriptional repressor ofmtrCDE, MtrA was found to bind with apparent lower affinity than MtrR to the same region. However, preincubation of MtrA with TX-100 prior to addition of the promoter-containing DNA probe increased MtrA binding and greatly reduced its dissociation from the promoter upon addition of MtrR. Two independent approaches (DNase I footprinting and a screen for bases important in MtrA binding) defined the MtrA-binding site 20–30 bp upstream of the known MtrR-binding site. Collectively, these results suggest that the MtrA and MtrR-binding sites are sterically close and that addition of an effector increases the affinity of MtrA for themtrCDEpromoter such that MtrR binding is negatively impacted. Our results provide a mechanism for transcriptional activation ofmtrCDEby MtrA and highlight the complexity of transcriptional control of drug efflux systems possessed by gonococci.IMPORTANCEAntibiotic resistance inNeisseria gonorrhoeaehas been increasing in recent years, such that in 2007 the Centers for Disease Control and Prevention listedN. gonorrhoeaeas a “superbug.” One of the major contributors to antibiotic resistance inN. gonorrhoeaeis the MtrCDE efflux pump. Until now, most work on the regulation of the genes encoding this efflux pump has been done on the transcriptional repressor, MtrR. This study is the first one to purify and define the DNA-binding ability of the transcriptional activator, MtrA. Understanding how levels of the MtrCDE efflux pump are regulated increases our knowledge of gonococcal biology and how the gonococcus can respond to various stresses, including antimicrobials.

scholarly journals Overcoming Multidrug Resistance in Bacteria Through Antibiotics Delivery in Surface-Engineered Nano-Cargos: Recent Developments for Future Nano-Antibiotics

2021 ◽  
Vol 9 ◽  
Author(s):  
Xinfu Yang ◽  
Wenxin Ye ◽  
Yajun Qi ◽  
Yin Ying ◽  
Zhongni Xia
Keyword(s):  
Drug Delivery ◽  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Surface Engineering ◽  
Bacterial Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Bacterial Cells ◽  
Recent Developments ◽  
Alternative Approaches

In the recent few decades, the increase in multidrug-resistant (MDR) bacteria has reached an alarming rate and caused serious health problems. The incidence of infections due to MDR bacteria has been accompanied by morbidity and mortality; therefore, tackling bacterial resistance has become an urgent and unmet challenge to be properly addressed. The field of nanomedicine has the potential to design and develop efficient antimicrobials for MDR bacteria using its innovative and alternative approaches. The uniquely constructed nano-sized antimicrobials have a predominance over traditional antibiotics because their small size helps them in better interaction with bacterial cells. Moreover, surface engineering of nanocarriers offers significant advantages of targeting and modulating various resistance mechanisms, thus owe superior qualities for overcoming bacterial resistance. This review covers different mechanisms of antibiotic resistance, application of nanocarrier systems in drug delivery, functionalization of nanocarriers, application of functionalized nanocarriers for overcoming bacterial resistance, possible limitations of nanocarrier-based approach for antibacterial delivery, and future of surface-functionalized antimicrobial delivery systems.

Recent Review on Subclass B1 Metallo-β-lactamases Inhibitors: Sword for Antimicrobial Resistance

2019 ◽  
Vol 20 (7) ◽  
pp. 756-762 ◽  
Author(s):  
Aditi Kaushik ◽  
Manish Kaushik ◽  
Viney Lather ◽  
J.S. Dua
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Antimicrobial Resistance ◽  
Global Health ◽  
Human Health ◽  
Microbial Pathogens ◽  
Present Review ◽  
Drug Molecules ◽  
Global Threat ◽  
Powerful Strategy

An emerging crisis of antibiotic resistance for microbial pathogens is alarming all the nations, posing a global threat to human health. The production of the metallo-β-lactamase enzyme is the most powerful strategy of bacteria to produce resistance. An efficient way to combat this global health threat is the development of broad/non-specific type of metallo-β-lactamase inhibitors, which can inhibit the different isoforms of the enzyme. Till date, there are no clinically active drugs against metallo- β-lactamase. The lack of efficient drug molecules against MBLs carrying bacteria requires continuous research efforts to overcome the problem of multidrug-resistance bacteria. The present review will discuss the clinically potent molecules against different variants of B1 metallo-β-lactamase.

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