How many general targets do antibacterial compounds have?
State the five general targets of antibacterial compounds and give an example of an antibiotic that acts on each target. Why are viruses not affected by antibacterial compounds?
What is the role of bacteriophage in antibiotic therapy?
Bacteriophage have been studied as a potential therapy for bacterial infection for over a hundred years and were used clinically after the First World War to treat various infections before antibiotics were discovered and became widespread (Kutter et al.,2015).
Are there antimicrobial agents targeting bacterial proteases?
Indeed, proteases have complex structures with potential drug binding pockets in active sites, protein–protein interaction sites, cofactor-binding sites or other allosteric sites. Despite these advantages, there are currently no approved antimicrobial agents targeting bacterial proteases.
Is there a role for perturbation in the development of antimicrobial drugs?
Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics.
Which aspect of a bacterium would be considered a drug target?
Abstract. The bacterial cell wall represents the primary target for antimicrobial agents.
What are other targets for bacterial treatment?
Therefore, according to its mechanism of action, the targets of antibacterial drugs include cell membrane, cell wall, protein synthesis, nucleic acid synthesis, and biological metabolic compound synthesis.
What would be good targets for antibiotics in bacteria?
In principal, there are three main antibiotic targets in bacteria: The cell wall or membranes that surrounds the bacterial cell. The machineries that make the nucleic acids DNA and RNA. The machinery that produce proteins (the ribosome and associated proteins)
What are the 5 bacterial targets for drug design?
Five bacterial targets have been exploited in the development of antimicrobial drugs: cell wall synthesis, protein synthesis, ribonucleic acid synthesis, deoxyribonucleic acid (DNA) synthesis, and intermediary metabolism.
Which two of the following are targets of antibacterial drugs that inhibit nucleic acid synthesis?
The nucleic acid synthesis inhibitors rifamycins and fluoroquinolones target bacterial RNA transcription and DNA replication, respectively.
Why are antibiotics effective against pathogenic bacteria?
Antibiotics work by disrupting bacterial cells in several ways, such as inhibiting the bacterium's ability to build its cell wall, blocking its reproduction, or interfering with its ability to store and use energy.
Why do antibiotics target bacteria and not human cells?
Official answer. Antibiotics work by interfering with the bacterial cell wall to prevent growth and replication of the bacteria. Human cells do not have cell walls, but many types of bacteria do, and so antibiotics can target bacteria without harming human cells.
How do antibiotics treat bacterial infections?
Antibiotics are medicines that fight infections caused by bacteria in humans and animals by either killing the bacteria or making it difficult for the bacteria to grow and multiply. Bacteria are germs. They live in the environment and all over the inside and outside of our bodies.
Why are antibiotics effective against bacteria but not against virus?
Viruses don't have cell walls that can be attacked by antibiotics; instead they are surrounded by a protective protein coat. Unlike bacteria, which attack your body's cells from the outside, viruses actually move into, live in and make copies of themselves in your body's cells.
What are the 5 modes of action for a chemicals in the inhibition of bacteria synthesis?
Five Basic Mechanisms of Antibiotic Action against Bacterial Cells:Inhibition of Cell Wall Synthesis.Inhibition of Protein Synthesis (Translation)Alteration of Cell Membranes.Inhibition of Nucleic Acid Synthesis.Antimetabolite Activity.
What are the 5 modes of action of antimicrobial drugs?
Basis of Antimicrobial Action Various antimicrobial agents act by interfering with (1) cell wall synthesis, (2) plasma membrane integrity, (3) nucleic acid synthesis, (4) ribosomal function, and (5) folate synthesis.
How do antibiotics target metabolic pathways?
Current antibiotics, derived mainly from natural sources, inhibit a narrow spectrum of cellular processes, namely DNA replication, protein synthesis, and cell wall biosynthesis.
What is a PT?
PT is a field that will provide innumerable benefits to science in general, but also to applied fields such as veterinary science, and of course medicine in particular by offering a possible solution to overcome the increasing problem of antibiotic-resistant pathogens. Combining antibiotic therapy and PT, the use of phage cocktails, or the use of phage protein products may be the most promising strategies for the treatment of bacterial infections involving phage. 83,85 Therefore, the focus of PT should not lie on the discovery of phages alone, but on investigating such strategies involving combinational therapies or phage products. Phages have a tremendous potential in reducing or eliminating the amount of infectious and resistant bacteria in environments such as hospital wards (intensive care unit) to reduce the risk of nosocomial infections. In addition, the use of phages in reducing the number of multi- and extreme drug-resistant bacteria in wastewater treatment plants could help us to fight the global threat of the so-called superbugs.
What is phage therapy?
The so-called phage therapy may be one of the most promising alternatives to treat infections caused by antibiotic-resistant bacteria, which are killed after infection by a phage . While phages that destroy the host by lysis are chosen for therapy, many pharmacological and immunological aspects of phages as medicines have not been established so far. The immune system plays an important role in a process called phage acceptance where both, innate and adaptive immune responses of the host are involved. However, not only medical aspects but also social ones such as lacking public awareness or acceptance, and lack of structured regulatory guidelines are challenges that have to be addressed in the near future to establish phage therapy as a reliable and safe alternative for the treatment of infections. This review focuses on the unique pharmacological and immunological aspects of phages used in therapy.
How do phages replicate?
Bacteriophages (phages) are viral particles that infect and replicate inside a bacterial cell with a high selectivity for a particular host , that is, a bacterium the virus is able to infect. 1 The lytic (virulent) and the lysogenic (temperate) cycles are two different viral reproduction mechanisms by which phages replicate inside the host bacterium. 2 The major difference between the two cycles is the integration of the viral nucleic acid into the bacterial genome during the lysogenic cycle, where the phage genome is multiplied as the host continues to grow and divide. During the lytic cycle, the viral genome is replicated immediately after infection without prior integration into the host DNA. 2 Lysogenic phages are able to enter a lytic phase, were replication and assembly is followed by cell lysis of the bacterium. Both lytic and lysogenic cycles produce a large amount of progeny. As the aim of phage therapy (PT) is the clearance of pathogens by killing the bacteria through lysis, phages in therapy have to be lytic, as the integration of the viral DNA is undesired. PT is not a new concept, described in the next paragraph; due to multidrug-resistant bacteria it is re-emerging after a century to kill pathogens as chemical drugs become ineffective. 1
Where are bacteriophages found?
Bacteriophages are the most abundant virobiota in the human body especially in the gut where show the largest diversity. 65,66 Together with their hosts, phages can be found in the oral, respiratory, gastrointestinal, and urinary tract, but also in the blood serum, where no microbes are found in a healthy individual. 67 Large numbers of phages are present in the infant intestines which decrease when the person grows up. Still, the amount of bacteriophages in the human body is enormous which might be providing a basis as biological stabilizers to the gut microbiota. 67 The most predominant phages in the human gut belong to the family of Caudovirales ( Myoviridae, Siphoviridae, and Podoviridae ), which is also the same family of phages used for PT. Studies on healthy individuals proved the existence of more than 1000 viral genotypes in the human gut. Most of these are microbial viruses, including the family of Caudovirales and prophages within bacterial genomes. 65
What are the roles of proteases in bacterial cell?
Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.
Which bacteria have a functional copy of clpP?
In contrast to most bacteria, two or more copies of clpP are found in actinobacteria and cyanobacteria and at least one functional copy is essential for viability. 37, 38 In Mycobacterium tuberculosis, clpP1 and clpP2 form an operon and both genes are essential.
Why are proteases important in pathogenesis?
Furthermore, the importance of proteases in bacterial pathogenesis offers an untapped vista of targets for new antivirulence drugs. Bacterial proteinases therefore are a great untapped frontier in the twenty-first century antibacterial drug discovery worthy of investigation and sustained effort.
What are the four families of intracellular proteolytic complexes?
Intracellular proteolytic complexes. There are four families of intracellular proteolytic complexes ubiquitous in eubacteria: Lon, HslUV (ClpQY), ClpXP and FtsH. In addition to these five, HtrA (DegP) is a periplasmic/secreted proteolytic complex, whereas the prokaryotic proteasome is found only in actinomycetes.
What is the drug that targets the hepatitis C virus?
For example, tipranavir (Aptivus; Pfizer/Boehringer Ingelheim) targets the HIV protease, boceprevir (Victrelis; Merck) targets the hepatitis C virus NS3-4A protease and bortezomid (Velcade; Milennium) is a proteasome inhibitor used for the treatment of multiple myeloma and mantle cell lymphoma. 14.
Why are there no new antibiotics?
In addition, the lack of new antimicrobial drugs coming to market and the paucity of companies investing in this therapeutic area conspire to threaten our ability to treat and prevent infectious diseases. One of the reasons for the lack of new antibiotics is a feeling that the traditional molecular target for antibiotics, cell wall biosynthesis, protein and DNA/RNA synthesis have perhaps been over-mined. 1 Over two decades of access to complete bacterial genomes and associated genome-scale tools promised a more rational target-based strategy to antibiotic discovery and the exploitation of new molecular targets; however, this approach has yet to fulfill its touted promise. Nevertheless, the current antibiotic crisis demands solutions including a renewed consideration of potential antibiotic targets and alternate therapeutic strategies. Bacterial proteases offer one such set of underexploited targets for new antimicrobial agents.
Is specificity important for protease inhibitors?
In the case of protease inhibitors aiming to act as suicide substrates, achieving specificity can be challenging, owing to conserved catalytic mechanisms. Indeed, a lack of specificity has been encountered in efforts to develop inhibitors of both the prokaryotic proteasome and the bacterial Lon protease.
Key Points
Bacteria encode a conserved set of proteolytic complexes: Clp, FtsH, Lon, HslUV, high-temperature requirement A serine protease (HtrA) and the prokaryotic proteasome.
Abstract
Proteases have been successfully targeted for the treatment of several diseases, including hypertension, type 2 diabetes, multiple myeloma, HIV and hepatitis C virus infections.
Main
In recent years, the dramatic rise in drug-resistant bacterial species has led organizations such as the World Health Organization to warn of a post-antibiotic era in which the current antimicrobial regimens will be largely ineffective against infectious pathogens.
Acknowledgements
We would like to thank S. Sieber and V. Dartois for personal communications that aided the impact of this work. Additionally, we thank M. Chao, K. Guinn, A. Trauner and J. Zhang for valuable editorial input during the revision process.
Author information
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02138, Massachusetts, USA
Glossary
A conserved set of bacterial enzymes that are responsible for the degradation of whole proteins into smaller, inactive polypeptides and amino acids.
What is the role of CGA in antioxidants?
It contains five active hydroxyl groups and one carboxyl group. The phenolic hydroxyl group structure reacts easily with free radicals and can form hydrogen radicals with an antioxidant effect to eliminate the activity of hydroxyl radicals and superoxide anions, therefore playing a strong antioxidant role. Antioxidant activity is one of the important activities of CGA, research shows ( Hu, Yu, & Zhao, 2006) that CGA has a scavenging effect on three kinds of reactive oxygen species ( − O 2 ,·OH and H 2 O 2 ). The scavenging effect and concentration is dose dependent. When the concentration is high, the scavenging effect on these three reactive oxygen species is obvious and stable. When the concentration is low, the scavenging effect on − O 2 · and ·OH deteriorates, even producing an oxidation-promoting effect.
What is CGA in medicine?
CGA is a kind of natural compound that is widely distributed and has many pharmacological activities: it has antioxidant, antiinflammatory, antibacterial, antiviral, hypoglycemic, lipid lowering, anticardiovascular, antimutagenic, antitumor effects, and can regulate the immune system. It has high clinical application value too. Its biological activity and function have been given increased attention and its application is now becoming more and more extensive. At present, research into CGA is gradually improving, for example, the production efficiency of CGA is showing signs of progress. However, the biosynthesis and regulation, pharmacological activity and development, and utilization of CGA are not systematic and are far from perfect. Its pharmacological activity, action mechanism, structure–activity relationship, toxicology, and clinical research still need further study to fully tap into its potential medicinal value, and make it play a greater role in medicine and the chemical, cosmetics, and food industries.
Does CGA kill bacteria?
In terms of antibacterial activity, CGA has broad-spectrum antibacterial activity, and has certain inhibitory on Escherichia coli, Staphylococcus aureus, yeast, Aspergillus niger, and Bacillus subtilis, as well as good resistance activity against Staphylococcus aureus and Escherichia coli. CGA has a stronger effect on fungi than bacteria, accompanied by a certain dose effect ( Zhu, Zhang, & Lo, 2004 ). It is clinically used for treating acute bacterial infection. Studies have found that CGA can destroy the biofilm of Pseudomonas aeruginosa and Aspergillus fumigatus and affect the normal growth of these strains to achieve a bacteriostatic effect ( Yan, Xiao, Zhou, & Yang, 2017 ). The bacteriostatic effect of CGA is mainly affected by temperature and increases with the increases in temperature, but when the temperature exceeds 60 °C, the bacteriostatic effect obviously decreases ( Karunanidhi, Thomas, van Belkum, & Neela, 2013 ). The early research has found that CGA has a significant inhibitory effect on the envelope synthesis of Stenotrophomonas maltophilia organisms. It is believed that CGA can be used as a safety antibacterial drug or a combination of antibacterial drugs to treat Stenotrophomonas maltophilia infection.
Does CGA reduce inflammation?
Its antiinflamma tory effect is another important biological property of CGA. Ohkawara, Takeda, and Nishihira (2017) studied CGA on inflammatory injury of pancreatic and lung tissues in mice with pancreatitis caused by l -arginine. CGA can reduce pancreatic-related tissues and inhibit the activity of the pancreatic enzyme. At the same time, it can significantly reduce the level of macrophage migration inhibitory factor in the pancreas and serum of mice, indicating that CGA has a strong antiinflammatory effect. Yun, Kang, and Lee (2012) studied the protective effect of CGA on liver ischemia/reperfusion injury. It was found that CGA could significantly improve liver function and pathological injury, and inhibit oxidative stress and tumor necrosis factor-α (TNF-α). The protective effect of CGA protects liver tissue by inhibiting inflammatory reaction and strengthening the antioxidant defense system. When Yu, Zhang, and Wang (2016) studied the effect of CGA on human periodontal ligament cells (hHDLCs), they found that CGA can significantly increase the activity of alkaline phosphatase, promote the proliferation of hHDLCs, promote the formation of mineralized nodules of hHDLCs, inhibit the expression of interleukin (IL)-6, and then inhibit the inflammatory response of human periodontal ligament cells. CGA has a strong antiinflammatory effect on arachidonic acid metabolism by inhibiting the activation of inflammatory factors such as HIF-1a, ICAM-1, VCAM-1, TNF-α, IL-6, and nuclear factor-kappa B (NK-κB) p65, thus protecting cerebral ischemia/reperfusion injury ( Miao, Cao, Li, Fang, & Miao, 2017 ).
Does CGA affect immune system?
CGA has certain immunomodulatory ability, but there is little research on its immunomodulatory effect at home and abroad. The activation of immune cells is the first link of the inflammatory response. CGA plays an immunomodulatory role by inhibiting the production of antiinflammatory cytokines by macrophages. In vitro studies showed that CGA could significantly enhance the proliferation of T-cells induced by influenza virus antigen and induce the production of IFN-γ and IFN-α from human lymphocytes and human peripheral blood leukocytes ( Jin et al., 2006 ). In addition, Dai Yi found that CGA can improve the metabolism and phagocytosis of peritoneal macrophages in mice, promote the release of NO, proinflammatory cytokines, IL-1β, and TNF-α, and inhibit the release of antiinflammatory cytokines IL-10 in a dose-dependent manner, playing an immunomodulatory role under normal and lipolipid-stimulated conditions ( Dai, Xu, Shangguan, & Zhao, 2015 ). Studies have shown that for allergic rhinitis in mice, CGA can significantly reduce the spleen index of mice, increase the thymus index and the content of IFN-γ in mouse nasal lavage, and reduce the IL-4 of mouse nasal lavage fluid. CGA significantly reduced the levels of histamine, IgE, IL-4, IL-5, and IL-10 in the serum of allergic rhinitis mice, increased the content of IFN-γ, and increased the value of IFN-γ/IL-4. It also downregulated the expression of IL-4, IL-5, and IL-10 mRNA in nasal mucosa of allergic rhinitis mice, upregulated the expression of IFN-γ mRNA, and exerted immunomodulatory effects through various immune cytokines to slow down allergic rhinitis in mice ( Li, Jiang, Liu, Di, & Hong, 2015 ).
Abstract
Defining the pharmacological target (s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis.
Substances
This work was supported by the InfectioPôle Sud (to RMC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
What is the effect of penicillin on the cell wall?
Penicillin binds to penicillin-binding proteins, thus inhibiting the transpeptidation reaction during cell wall synthesis.
What is the function of bacitracin?
Bacitracin blocks the movement of peptidoglycan subunits from the cytoplasm to the exterior of the cell. Bacitracin inserts into the plasma membrane , causing cell lysis. Bacitracin blocks the movement of peptidoglycan subunits from the cytoplasm to the exterior of the cell.
What is a superinfection?
A superinfection is a type of secondary infection that develops when antibiotics taken to treat a particular pathogen do not completely kill all of that original pathogen. A secondary infection is a type of superinfection that develops when the pathogen mutates in response to the antimicrobial agent.
What is secondary infection?
A secondary infection is a type of superinfection that develops when antibiotics are not given. A superinfection is a type of secondary infection that can develop when antibiotics kill much of the patient's normal flora.