Translational control of antibiotic resistance

Witzky, Anne; Tollerson, Rodney; Ibba, Michael

doi:10.1098/rsob.190051

Cited by 22 publications

(17 citation statements)

References 124 publications

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“…Some bacteria are naturally resistant to antibiotics, while others acquire resistance mainly through the misuse of antibiotics and the emergence of new resistant strains [ 24 ]. The mechanism of antibacterial resistance ranges from accelerating antibiotics efflux through bacterial efflux pumps so as to decrease the time required for medication to diffuse inside bacteria [ 25 ], alteration of bacterial porins' structure which decreases bacterial permeability to antibiotic influx [ 26 ], destruction of antibacterial agents by hydrolytic enzymes [ 25 ], to alteration of binding sites for antibiotics [ 27 ]. For bacteria, they may fight antibiotics by one mechanism or by combining more than one to produce their resistance [ 25 ].…”

Section: Mechanism Of Bacterial Resistancementioning

confidence: 99%

Review on the Antibacterial Mechanism of Plant-Derived Compounds against Multidrug-Resistant Bacteria (MDR)

Jubair

Rajagopal

Chinnappan

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Microbial resistance has progressed rapidly and is becoming the leading cause of death globally. The spread of antibiotic-resistant microorganisms has been a significant threat to the successful therapy against microbial infections. Scientists have become more concerned about the possibility of a return to the pre-antibiotic era. Thus, searching for alternatives to fight microorganisms has become a necessity. Some bacteria are naturally resistant to antibiotics, while others acquire resistance mainly by the misuse of antibiotics and the emergence of new resistant variants through mutation. Since ancient times, plants represent the leading source of drugs and alternative medicine for fighting against diseases. Plants are rich sources of valuable secondary metabolites, such as alkaloids, quinones, tannins, terpenoids, flavonoids, and polyphenols. Many studies focus on plant secondary metabolites as a potential source for antibiotic discovery. They have the required structural properties and can act by different mechanisms. This review analyses the antibiotic resistance strategies produced by multidrug-resistant bacteria and explores the phytochemicals from different classes with documented antimicrobial action against resistant bacteria, either alone or in combination with traditional antibiotics.

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Section: Mechanism Of Bacterial Resistancementioning

confidence: 99%

Review on the Antibacterial Mechanism of Plant-Derived Compounds against Multidrug-Resistant Bacteria (MDR)

Jubair

Rajagopal

Chinnappan

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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“…Solithromycin (Solithera) is in phase 3 and expected to have activity against MDR Neisseria gonorrhoeae, and nafithromycin (WCK 4873) is in phase 2. While these new ketolides are not more potent per se than the current ones, they appear not to induce the expression of the corresponding ARE genes to the same degree [23,[76][77][78]. However, these new ketolides are less effective when erm genes are expressed constitutively [78,79].…”

Section: Pharmaceutical Pipeline and Implications For Futurementioning

confidence: 70%

“…Unlike target alteration (AB binding site mutation or modification, e.g., ribosome methylation by specialized methyltransferases), target protection does not involve a permanent change to the target. In case of a target as conserved and functionally fine-tuned as the ribosome, permanent changes that alter the target in order to reduce or abolish AB binding are often accompanied by a fitness cost due to reduced functionality of the highly conserved centers of the ribosome [23]. Hence, there tends to be a trade-off between optimal fitness and ARE.…”

Section: Ribosome Protection Proteinsmentioning

confidence: 99%

“…For example, to overcome the fitness cost resulting from the methylation of 23S rRNA residue A2058 that confers resistance to macrolides, ketolides, lincosamides, and S B , the corresponding Erm methyltransferases are not expressed constitutively but are induced only in the presence of corresponding AB [24]. This inducible system allows S. aureus to survive in the presence of an AB yet still maintain optimal growth when conditions are favorable [23]. In contrast, ribosome protection results from persistent or repeated direct physical interaction between ribosome and specialized ribosome protection proteins (RPP) that does not introduce a permanent change to the ribosome in order to rescue the translation apparatus from AB inhibition.…”

Section: Ribosome Protection Proteinsmentioning

confidence: 99%

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Ribosome Protection Proteins—“New” Players in the Global Arms Race with Antibiotic-Resistant Pathogens

Ero

Yan

Gao

2021

IJMS

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Bacteria have evolved an array of mechanisms enabling them to resist the inhibitory effect of antibiotics, a significant proportion of which target the ribosome. Indeed, resistance mechanisms have been identified for nearly every antibiotic that is currently used in clinical practice. With the ever-increasing list of multi-drug-resistant pathogens and very few novel antibiotics in the pharmaceutical pipeline, treatable infections are likely to become life-threatening once again. Most of the prevalent resistance mechanisms are well understood and their clinical significance is recognized. In contrast, ribosome protection protein-mediated resistance has flown under the radar for a long time and has been considered a minor factor in the clinical setting. Not until the recent discovery of the ATP-binding cassette family F protein-mediated resistance in an extensive list of human pathogens has the significance of ribosome protection proteins been truly appreciated. Understanding the underlying resistance mechanism has the potential to guide the development of novel therapeutic approaches to evade or overcome the resistance. In this review, we discuss the latest developments regarding ribosome protection proteins focusing on the current antimicrobial arsenal and pharmaceutical pipeline as well as potential implications for the future of fighting bacterial infections in the time of “superbugs.”

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“…Spread of antibiotic resistance in bacteria is one of the most urgent issues in medicine, wellknown and long used antibiotics are losing their efficacy over time. The most promising ways to overcome this problem are creating analogs based on existing antibiotics, searching for novel natural substances with antibacterial activity, as well as thorough study of antibacterials and the resistance mechanisms to them (Nicolaou and Rigol, 2018;Witzky et al, 2019). Amicoumacin A (Ami) is a substance with the potential to become a new therapeutic antimicrobial agent.…”

Section: Introductionmentioning

confidence: 99%

Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation

et al. 2021

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Amicoumacin A (Ami) halts bacterial growth by inhibiting the ribosome during translation. The Ami binding site locates in the vicinity of the E-site codon of mRNA. However, Ami does not clash with mRNA, rather stabilizes it, which is relatively unusual and implies a unique way of translation inhibition. In this work, we performed a kinetic and thermodynamic investigation of Ami influence on the main steps of polypeptide synthesis. We show that Ami reduces the rate of the functional canonical 70S initiation complex (IC) formation by 30-fold. Additionally, our results indicate that Ami promotes the formation of erroneous 30S ICs; however, IF3 prevents them from progressing towards translation initiation. During early elongation steps, Ami does not compromise EF-Tu-dependent A-site binding or peptide bond formation. On the other hand, Ami reduces the rate of peptidyl-tRNA movement from the A to the P site and significantly decreases the amount of the ribosomes capable of polypeptide synthesis. Our data indicate that Ami progressively decreases the activity of translating ribosomes that may appear to be the main inhibitory mechanism of Ami. Indeed, the use of EF-G mutants that confer resistance to Ami (G542V, G581A, or ins544V) leads to a complete restoration of the ribosome functionality. It is possible that the changes in translocation induced by EF-G mutants compensate for the activity loss caused by Ami.

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Translational control of antibiotic resistance

Cited by 22 publications

References 124 publications

Review on the Antibacterial Mechanism of Plant-Derived Compounds against Multidrug-Resistant Bacteria (MDR)

Review on the Antibacterial Mechanism of Plant-Derived Compounds against Multidrug-Resistant Bacteria (MDR)

Ribosome Protection Proteins—“New” Players in the Global Arms Race with Antibiotic-Resistant Pathogens

Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation

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