Directions in the development of modern and promising antimicrobial agents (original) (raw)
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Novel targets to develop new antibacterial agents and novel alternatives to antibacterial agents
2019
Antibacterial agents have saved many lives and helped the growth of modern medicine over the past half century. The emergence of drug resistance, jeopardizing the effectiveness of these life-saving treatments. This clearly highlights the urgent need for new and improved antibacterial drugs with a novel target and new molecular structure agent to obviate cross-resistance. This paper reviewed the possible new ways to discover novel antibacterial agents. The most widely studied new bacterial targets for novel drug development are quorum sensor biosynthesis, bacterial virulence factor, bacteria cell division machinery, Bacterial cell wall synthesis, PDF inhibitor, isoprenoid biosynthesis, shikimate synthesis pathway, biofilm synthesis and fatty acid biosynthesis. These new discovery routes have given rise to agents that are in preclinical trials. This review also discusses the alternatives approaches that act bacteria or any approaches that target the host. The most advanced approaches that are on clinical development are phages and other approaches that are on preclinical development are antimicrobial peptides. These alternatives ways may use as adjunctive therapies, which suggest that conventional antibacterial agents are still essential.
Anti-quorum sensing agents: a potential alternative for antibiotics
International Journal of Agricultural and Applied Sciences
Quorum sensing (QS) is a bacterial cell to cell communication, which helps bacteria to mount population-density-dependent infection to overcome the defence responses from host. In this mechanism some diffusible chemical signalling compounds are involved, known as autoinducers, which are directly proportional to the population cell density. The main role of QS is to coordinate the expression of several collective traits, including the production of virulence factors, secondary metabolites with antimicrobial activity, pigment production, siderophore production, epiphytic fitness, bioluminescence, plasmid transfer, motility and biofilm formation. Due to the growing bacterial resistance to the antibiotics that have been overused, it has become necessary to search for alternative antimicrobial therapies. One of them is anti-quorum sensing agents/anti-biofilm agents/quorum sensing inhibitors that disrupts the bacterial communication. This study discusses the various QS-disrupting mechanis...
New Targets for Antibacterial Agents
The alarming increase and spread of resistance among emerging and re-emerging bacterial pathogens to all clinically useful antibiotics is one of the most serious public health problems of the last decade. Thus, the search for new antibacterials directed toward new targets is not only a continuous process but also, at this time, an urgent necessity. Recent advances in molecular biological technologies have significantly increased the ability to discover new antibacterial targets and quickly predict their spectrum and selectivity. The most extensively evaluated bacterial targets for drug development are: quorum sensor biosynthesis; the two component signal transduction(TCST) systems; bacteria division machinery; the shikimate pathway; isoprenoid biosynthesis and fatty acid biosynthesis.
Quorum sensing inhibitory drugs as next generation antimicrobials: worth the effort?
Current infectious disease reports, 2008
Bacterial resistance poses a major challenge to the development of new antimicrobial agents. Conventional antibiotics have an inherent obsolescence because they select for development of resistance. Bacterial infections have again become a serious threat in developed countries. Particularly, elderly, immunocompromised, and hospitalized patients are susceptible to infections caused by bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. These bacteria form chronic, biofilm-based infections, which are challenging because bacterial cells living as biofilms are more tolerant to antibiotics than their planktonic counterparts. Therefore, research should identify new antimicrobial agents and their corresponding targets to decrease the biofilm-forming capability or persistence of the infectious bacteria. Here, we review one such drug target: bacterial cell-to-cell communication systems, or quorum sensing.
International Journal of Antimicrobial Agents, 2013
New unconventional approaches to the development of antimicrobial drugs must target inhibition of infection stages leading to host colonisation or virulence itself, rather than bacterial viability. Amongst the most promising unconventional targets for the development of new antimicrobial drugs is bacterial adherence and biofilm formation as well as their control system, the quorum-sensing (QS) system, a mechanism of communication used to co-ordinate bacterial activities. Here we describe the evaluation of synthetic organic compounds as bacterial biofilm inhibitors against a panel of clinically relevant Gram- positive and Gram-negative bacterial strains. This approach has successfully allowed the identification of five compounds (GEt, GHex, GOctad, G19 and C33) active not only against bacterial biofilms but also displaying potential to be used as antagonists and/or inhibitors of bacterial QS.
Virulence-targeted Antibacterials: Concept, Promise, and Susceptibility to Resistance Mechanisms
Chemical biology & drug design, 2015
In view of the relentless increase in antibiotic resistance in human pathogens, efforts are needed to safeguard our future therapeutic options against infectious diseases. In addition to regulatory changes in our antibiotic use, this will have to include the development of new therapeutic compounds. One area that has received growing attention in recent years is the possibility to treat or prevent infections by targeting the virulence mechanisms that render bacteria pathogenic. Antivirulence targets include bacterial adherence, secretion of toxic effector molecules, bacterial persistence through biofilm formation, quorum sensing and immune evasion. Effective small-molecule compounds have already been identified that suppress such processes. In this review, we discuss the susceptibility of such compounds to the development of resistance, by comparison with known resistance mechanisms observed for classical bacteriostatic or bacteriolytic antibiotics, and by review of available experi...
Antibiotics, 2019
Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of the development of virulence inhibitors, inhibition of quorum sensing (QS) is a promising route because various important features in bacterial physiology and virulence are mediated by QS-dependent gene expression. Methods: Forty-five pharmacological agents, encompassing a wide variety of different chemical structures and mechanisms of action, were tested during our experiments. The antibacterial activity of the compounds was tested using the broth microdilution method. Screening and semi-quantitative assessment of QS-inhibition by the compounds was performed using QS-signal molecule-producing and indicator strains. Results: Fourteen pharmaceutical agents showed antibacterial activity in the tested concentration range, while eight drugs (namely 5-fluorouracil, metamizole-sodium, cisplatin, methotrexate, bleomycin, promethazine, chlorpromazine, and thioridazine) showed dose-dependent QS-inhibitory activity in the in vitro model systems applied during the experiments. Conclusions: Virulence inhibitors represent an attractive alternative strategy to combat bacterial pathogens more efficiently. Some of the tested compounds could be considered potential QS-inhibitory agents, warranting further experiments involving additional model systems to establish the extent of their efficacy.
Asian Journal of Pharmaceutical and Clinical Research, 2019
The unresponsive use of antibiotics led to the appearance of multiple drug-resistant bacteria strains. Studying the mechanism by which bacteria can resist antibiotics, the so called quorum sensing and biofilm formation, enabled the researchers to find bioactive compounds, derived from eukaryotes and prokaryotes. The disrupt of this mechanism is called quorum sensing inhibitors or quorum quenchers. This article provides an overview on the current research done on such bioactive compounds, the possible use of them as antibiotic alternatives, what are the advantage and disadvantages, the source from which it has been extracted, and how it may succeed to overcome bacterial resistance. The recommendation of researchers is to use some of these natural antimicrobial compounds combined to lower doses of antibiotics for treatment, the fastest way to limit the adverse effects of the exploitation of antibiotics and to avoid bacterial resistance.
It is the time for quorum sensing inhibition as alternative strategy of antimicrobial therapy
Cell Communication and Signaling
Multiple drug resistance poses a significant threat to public health worldwide, with a substantial increase in morbidity and mortality rates. Consequently, searching for novel strategies to control microbial pathogenicity is necessary. With the aid of auto-inducers (AIs), quorum sensing (QS) regulates bacterial virulence factors through cell-to-cell signaling networks. AIs are small signaling molecules produced during the stationary phase. When bacterial cultures reach a certain level of growth, these molecules regulate the expression of the bound genes by acting as mirrors that reflect the inoculum density.Gram-positive bacteria use the peptide derivatives of these signaling molecules, whereas Gram-negative bacteria use the fatty acid derivatives, and the majority of bacteria can use both types to modulate the expression of the target gene. Numerous natural and synthetic QS inhibitors (QSIs) have been developed to reduce microbial pathogenesis. Applications of QSI are vital to huma...