Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design

2018 ◽  
Vol 87 (1) ◽  
pp. 451-478 ◽  
Author(s):  
Jinzhong Lin ◽  
Dejian Zhou ◽  
Thomas A. Steitz ◽  
Yury S. Polikanov ◽  
Matthieu G. Gagnon
Keyword(s):  
Protein Synthesis ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Resistance Mechanisms ◽  
Public Health Care ◽  
Drug Resistant ◽  
Protein Synthesis Inhibitors ◽  
Antimicrobial Drugs ◽  
Modes Of Action ◽  
Action Mechanisms

Genetic information is translated into proteins by the ribosome. Structural studies of the ribosome and of its complexes with factors and inhibitors have provided invaluable information on the mechanism of protein synthesis. Ribosome inhibitors are among the most successful antimicrobial drugs and constitute more than half of all medicines used to treat infections. However, bacterial infections are becoming increasingly difficult to treat because the microbes have developed resistance to the most effective antibiotics, creating a major public health care threat. This has spurred a renewed interest in structure-function studies of protein synthesis inhibitors, and in few cases, compounds have been developed into potent therapeutic agents against drug-resistant pathogens. In this review, we describe the modes of action of many ribosome-targeting antibiotics, highlight the major resistance mechanisms developed by pathogenic bacteria, and discuss recent advances in structure-assisted design of new molecules.

scholarly journals Antimicrobial Resistance in Oral biofilm: Challenges and Alternatives

2021 ◽  
Vol 12 (1) ◽  
pp. 349-356
Author(s):  
Satish Kumar Sharma ◽  
Shmmon Ahmad
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Bacterial Biofilm ◽  
Bacterial Biofilms ◽  
Target Cells ◽  
Bacterial Cells ◽  
Antimicrobial Drugs ◽  
Oral Infections

Bacterial biofilm has been a major contributor to severe bacterial infections in humans. Oral infections have also been associated with biofilm-forming microbes. Several antimicrobial strategies have been developed to combat bacterial biofilms. However, the complexity of the oral cavity has made it difficult to use common drug treatments. Most effective ways to control normal bacterial infections are rendered ineffective for bacterial biofilms. Due to limited drug concentration availability, drug neutralization or altered phenotype of bacterial cells, different drug have been ineffective to identify the target cells. This leads to the development of the multifaceted phenomenon of antimicrobial resistance (AMR). Biofilm research done so far has been focused on using antimicrobial drugs to target molecular mechanisms of cells. The severity and resistance mechanisms of extracellular matrix (ECM) have been underestimated. The present study describes different antimicrobial strategies with respect to their applications in dental or oral infections. A prospective strategy has been proposed targeting ECM which is expected to provide an insight on biofilm obstinacy and antimicrobial resistance.

scholarly journals Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

2012 ◽  
Vol 56 (11) ◽  
pp. 5433-5441 ◽  
Author(s):  
Miles C. Duncan ◽  
Roger G. Linington ◽  
Victoria Auerbuch
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Magic Bullet ◽  
Antimicrobial Drugs ◽  
Type Three Secretion System ◽  
Type Three Secretion

ABSTRACTThe recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by “magic bullet” drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

The Application of Nucleic Acids and Nucleic Acid Materials in Antimicrobial Research

2021 ◽  
Vol 16 (1) ◽  
pp. 66-73 ◽  
Author(s):  
Yue Sun ◽  
Lingxian Meng ◽  
Yuxin Zhang ◽  
Dan Zhao ◽  
Yunfeng Lin
Keyword(s):  
Nucleic Acids ◽  
Dna Sequences ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Metal Oxide Nanoparticles ◽  
Resistant Bacteria ◽  
Multiple Drug ◽  
Potential Candidate ◽  
Drug Resistant ◽  
Mortality And Morbidity

Due to the misuse of antibiotics, multiple drug-resistant pathogenic bacteria have increasingly emerged. This has increased the difficulty of treatment as these bacteria directly affect public health by diminishing the potency of existing antibiotics. Developing alternative therapeutic strategies is the urgent need to reduce the mortality and morbidity related to drug-resistant bacterial infections. In the past 10 to 20 years, nanomedicines have been widely studied and applied as an antibacterial agent. They have become a novel tool for fighting resistant bacteria. The most common innovative substances, metal and metal oxide nanoparticles (NPs), have been widely reported. Until recently, DNA nanostructures were used alone or functionalized with specific DNA sequences by many scholars for antimicrobial purposes which were alternatively selected as therapy for severe bacterial infections. These are a potential candidate for treatments and have a considerable role in killing antibiotic-resistant bacteria. This review involves the dimensions of multidrug resistance and the mechanism of bacteria developing drug resistance. The importance of this article is that we summarized the current study of nano-materials based on nucleic acids in antimicrobial use. Meanwhile, the current progress and the present obstacles for their antibacterial and therapeutic use and special function of stem cells in this field are also discussed.

scholarly journals Bactericidal Activity of ACH-702 against Nondividing and Biofilm Staphylococci

2012 ◽  
Vol 56 (7) ◽  
pp. 3812-3818 ◽  
Author(s):  
Steven D. Podos ◽  
Jane A. Thanassi ◽  
Melissa Leggio ◽  
Michael J. Pucci
Keyword(s):  
Protein Synthesis ◽  
Stationary Phase ◽  
Bactericidal Activity ◽  
Bacterial Infections ◽  
De Novo ◽  
Viable Cell ◽  
Bacterial Cells ◽  
Protein Synthesis Inhibitors ◽  
Content Type ◽  
Cell Counts

ABSTRACTMany bacterial infections involve slow or nondividing bacterial growth states and localized high cell densities. Antibiotics with demonstrated bactericidal activity rarely remain bactericidal at therapeutic concentrations under these conditions. The isothiazoloquinolone (ITQ) ACH-702 is a potent, bactericidal compound with activity against many antibiotic-resistant pathogens, including methicillin-resistantStaphylococcus aureus(MRSA). We evaluated its bactericidal activity under conditions where bacterial cells were not dividing and/or had slowed their growth. AgainstS. aureuscultures in stationary phase, ACH-702 showed concentration-dependent bactericidal activity and achieved a 3-log-unit reduction in viable cell counts within 6 h of treatment at ≥16× MIC values; in comparison, the bactericidal quinolone moxifloxacin and the additional comparator compounds vancomycin, linezolid, and rifampin at 16× to 32× MICs showed little or no bactericidal activity against stationary-phase cells. ACH-702 at 32× MIC retained bactericidal activity against stationary-phaseS. aureusacross a range of inoculum densities. ACH-702 did not kill cold-arrested cells yet remained bactericidal against cells arrested by protein synthesis inhibitors, suggesting that its bactericidal activity against nondividing cells requires active metabolism but notde novoprotein synthesis. ACH-702 also showed a degree of bactericidal activity at 16× MIC againstS. epidermidisbiofilm cells that was superior to that of moxifloxacin, rifampin, and vancomycin. The bactericidal activity of ACH-702 against stationary-phase staphylococci and biofilms suggests potential clinical utility in infections containing cells in these physiological states.

scholarly journals Mechanism of BceAB-type transporter: Resistance by lipid II flipping

2020 ◽  
Author(s):  
Julia Zaschke-Kriesche ◽  
Sandra Unsleber ◽  
Irina Voitsekhovskaia ◽  
Andreas Kulik ◽  
Lara V. Behrmann ◽  
...  
Keyword(s):  
Cell Wall ◽  
Antimicrobial Peptides ◽  
Streptococcus Agalactiae ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Human Pathogenic Bacteria ◽  
Lipid Ii ◽  
Multiresistant Bacteria

AbstractTreatment of bacterial infections are the great challenge of our era due to the evolved resistance mechanisms against antibiotics. The Achilles heel of bacteria is the cell wall especially during the needs of its synthesis and cell division. Here lipid II is an essential cell wall precursor component synthesized in the cytosol and flipped into the outer leaflet of the membrane prior to its incorporation into the cell wall.Compounds targeting the cell wall or its biosynthesis precursors have been around for decades and have been used as antibiotics against bacterial infections like meningitis, pneumonia and endocarditis. Antimicrobial peptides (AMPs) have proven to be a promising weapon against multiresistant bacteria. However, the Bacitracin efflux (BceAB)-type ATP binding cassette transporters expressed in the membrane of human pathogenic bacteria have been shown to confer resistance to these alternative antibiotics, thereby hampering their medical development.In Streptococcus agalactiae COH1 the BceAB-type transporter NsrFP (SaNsrFP) confers high-level resistance against the antimicrobial peptide nisin, a member of the lantibiotic subfamily. We showed that SaNsrFP provides a novel resistance mechanism by flipping lipid II back into the cytosol, thereby preventing the binding of nisin as well as other lipid II targeting compounds. This is intriguing since a relatively simple reaction mediates resistance to human pathogenic bacteria to lipid II targeting antibiotics, regardless of their structure.Significance StatementThe ABC-transporter NsrFP from Streptococcus agalactiae (SaNsrFP) belongs to the BceAB-type transporters. Several BceAB-type transporters are known to confer resistance against multiple antimicrobial peptides. In this study a new resistance mechanism was identified, which is based on the reduction of the number of cell wall precursor lipid II molecules on the cell surface mediated by SaNsrFP. SaNsrFP flips lipid II, which are considered to be the target for many antibiotics, back into the cytoplasm. With this newly gained knowledge about the resistance mechanism of BceAB-type transporters, novel strategies can be established to overcome or bypass this resistance in human pathogenic bacteria.

scholarly journals Investigating the mode of action of tuberculosis drugs using hypersensitive mutants of Mycobacterium smegmatis

2021 ◽  
Author(s):  
◽  
Richard Laurence Campen
Keyword(s):  
High Throughput ◽  
Mode Of Action ◽  
Drug Hypersensitivity ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Resistant ◽  
Primary Target ◽  
Modes Of Action ◽  
Increased Sensitivity ◽  
High Throughput Assay

<p>Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is the leading cause of death and disease by a bacterial pathogen worldwide. The growing incidence of drug resistant TB, especially multi-drug resistant TB highlights the need for new drugs with novel modes of action. Current treatment of TB involves a multi-drug regimen of four drugs including isoniazid and rifampicin, both of which were discovered over 40 years ago. Bedaquiline is one of the first novel TB drugs to enter clinical trials since the discovery of rifampicin, and has shown excellent activity against drug resistant TB. Although isoniazid and rifampicin are well established anti-TB drugs, significant gaps in knowledge regarding their modes of action exist. Furthermore, little information on the mode of action of the novel drug bedaquiline is known beyond its primary target. Characterisation of drug mode of action facilitates rational modifications of drugs to improve the treatment of TB.  The aim of this study was to identify novel aspects of the modes of action of isoniazid, rifampicin, and bedaquiline by characterising drug hypersensitive mutants of M. smegmatis mc²155. A sub-saturated M. smegmatis mc²155 transposon mutant collection with 1.1-fold genome coverage (7680 mutants) was constructed, with this collection estimated to contain mutations in 73.2% of all genes capable of maintaining a transposon insertion (non-essential genes). A high-throughput assay was developed for screening the collection, and mutants related to known drug mode of action were identified for isoniazid (ahpC and eccCa₁) and bedaquiline (atpB). Additionally, known mechanisms of drug inactivation were identified for isoniazid (nudC), rifampicin (arr and lspA), and bedaquiline (mmpL5). The finding that transposon mutants of nudC are hypersensitive to isoniazid independently validated the recent discovery of the role of NudC in basal isoniazid resistance by Wang et al. (2011). The remaining genes identified in this thesis represent potentially novel aspects of the modes of action or resistance mechanisms of these drugs.  Cross-sensitivity to other drugs indicated that the mechanism of sensitivity was drug specific for the mutants examined. Differential-sensitivity testing against drug analogues revealed that Arr is involved in resistance to the rifampicin analogue rifapentine as well, indicating that Arr can detoxify rifapentine similar to rifampicin. The nudC mutant showed increased sensitivity to a range of isoniazid analogues, indicating that it can detoxify these analogues similar to the parent compound. Interestingly six analogues were found to be less active against the nudC mutant than expected. A number of overexpression strains were tested against these six analogues; a nudC overexpression strain, and a strain overexpressing inhA, the primary target for isoniazid. Overexpression of nudC as well inhA increased the resistance of WT to isoniazid, but failed to increase resistance to three of the analogues, NSC27607, NSC33759, and NSC40350. Isoniazid is a prodrug and is activated by the peroxidase/catalase enzyme KatG. Overexpression of katG resulted in increased isoniazid sensitivity, as well as increased sensitivity to NSC27607, NSC33759, and NSC40350. Together these results suggest that NSC27607, NSC33759, and NSC40350 are activated by KatG, but that InhA is not the primary target. Additionally the inability of NudC overexpression to confer resistance suggests these analogues are not acting via a NAD adduct, the mechanism by which isoniazid inhibits InhA. These results suggest that there are other toxic metabolites being produced by KatG activation of these three analogues.  In conclusion, characterisation of mutants identified in a high-throughput assay for drug hypersensitivity identified genes involved in the modes of action or resistance mechanisms for isoniazid, rifampicin, and bedaquiline. Additionally, a number of novel genes were identified that have no known connections to the known modes of action or resistance mechanisms for these drugs. Further testing of a nudC mutant revealed three isoniazid analogues that appear to inhibit growth of M. smegmatis mc²155 independent of InhA, the primary target of isoniazid. This study has successfully demonstrated that screening for drug hypersensitivity can generate novel information on drug mode of action and resistance mechanisms. This information can ultimately be used to help drive the development of new drugs, and improve treatment of TB.</p>

scholarly journals Reduced Lytic Activity of Bacteriophages in Presence of Antibiotics Targeting Bacterial Protein Synthesis

2021 ◽  
Author(s):  
Medhavi Vashisth ◽  
Shikha Yashveer ◽  
Nitin Virmani ◽  
Bidhan Chandra Bera ◽  
Rajesh Kumar Vaid ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Bacterial Infections ◽  
Antagonistic Effect ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Bacterial Protein ◽  
Protein Synthesis Machinery ◽  
Multiple Drug Resistant ◽  
Bacterial Protein Synthesis ◽  
Careful Assessment

Combination therapy of bacteriophage and antibiotics offers promise to treat multiple drug resistant bacterial infections through phage antibiotic synergy. However, its usage requires careful assessment as most antibiotics with mechanisms dependent upon inhibiting cell growth through interfering bacterial protein synthesis machinery were found to have an antagonistic effect on phage activity.

scholarly journals Development of a Tetracycline Resistant Strain of E. coli Sensitive to Ultraviolet Radiation

2014 ◽  
Vol 3 (1) ◽  
pp. 63-68
Author(s):  
Meredith Joy Reesor ◽  
Isaac Joseph King ◽  
Jeffrey Copeland
Keyword(s):  
Escherichia Coli ◽  
Protein Synthesis ◽  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Resistant Strain ◽  
Bacterial Infections ◽  
Present Report ◽  
Medical Community ◽  
Protein Synthesis Inhibitors ◽  
E Coli

Multidrug resistance bacteria pose a significant threat to human health and the efforts of the medical community.  Given our reliance on antibiotics for therapeutic treatment of bacterial infections it is imperative to understand the mechanism by which bacteria develop antibiotic resistance.  In the present report we develop a strain of Escherichia coli capable of resisting high levels of tetracycline and other protein synthesis inhibitors.  Furthermore the tetracycline resistant strain is approximately 1/3rd in length and is sensitive to UV radiation.

scholarly journals Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase

2016 ◽  
Vol 60 (10) ◽  
pp. 6271-6280 ◽  
Author(s):  
Andrés Palencia ◽  
Xianfeng Li ◽  
Wei Bu ◽  
Wai Choi ◽  
Charles Z. Ding ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mycobacterium Tuberculosis ◽  
Cell Activity ◽  
Trna Synthetase ◽  
Protein Synthesis Inhibitor ◽  
Drug Resistant ◽  
Protein Synthesis Inhibitors ◽  
Synthesis Inhibitor ◽  
Content Type

ABSTRACTThe recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains ofMycobacterium tuberculosishighlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective againstM. tuberculosisin TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), toM. tuberculosisLeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity againstM. tuberculosis. Importantly, their good oral bioavailability translates intoin vivoefficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

Antibiotics Targeting the 30S Ribosomal Subunit: A Lesson from Nature to Find and Develop New Drugs

2019 ◽  
Vol 18 (24) ◽  
pp. 2080-2096 ◽  
Author(s):  
Anna Maria Giuliodori ◽  
Roberto Spurio ◽  
Pohl Milón ◽  
Attilio Fabbretti
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Bacterial Infections ◽  
Negative Impact ◽  
Ribosomal Subunit ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Screening Tests ◽  
Initiation Step ◽  
Resistant Strains

The use of antibiotics has revolutionized medicine, greatly improving our capacity to save millions of lives from otherwise deadly bacterial infections. Unfortunately, the health-associated benefits provided by antibiotics have been counteracted by bacteria developing or acquiring resistance mechanisms. The negative impact to public health is now considered of high risk due to the rapid spreading of multi-resistant strains. More than 60 % of clinically relevant antibiotics of natural origin target the ribosome, the supramolecular enzyme which translates the genetic information into proteins. Although many of these antibiotics bind the small ribosomal subunit, only a few are reported to inhibit the initiation of protein synthesis, with none reaching commercial availability. Counterintuitively, translation initiation is the most divergent phase of protein synthesis between prokaryotes and eukaryotes, a fact which is a solid premise for the successful identification of drugs with reduced probability of undesired effects to the host. Such a paradox is one of its kind and deserves special attention. In this review, we explore the inhibitors that bind the 30S ribosomal subunit focusing on both the compounds with proved effects on the translation initiation step and the underreported translation initiation inhibitors. In addition, we explore recent screening tests and approaches to discover new drugs targeting translation.

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