14.7 Current Strategies for Antimicrobial Discovery
3 min read•june 18, 2024
Antimicrobial discovery is evolving rapidly, using high-tech methods like automated screening and to find new drugs. Scientists are exploring untapped sources like oceans and unculturable microbes, hoping to uncover novel compounds that can fight resistant bacteria.
The search isn't just about killing germs anymore. Researchers are getting creative, looking for ways to block bacterial defenses, stop them from causing harm, or even repurpose existing drugs. It's a race against time to outsmart superbugs and keep our medicines working.
Current Strategies for Antimicrobial Discovery
Methods of antimicrobial discovery
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- (HTS)
- Automated process rapidly assesses large numbers of compounds for antimicrobial activity using robotics, data processing software, and sensitive detectors
- Screens large libraries of natural and synthetic compounds to identify "hits" that exhibit desired antimicrobial properties (inhibition of bacterial growth, biofilm formation, or virulence factors)
- (isolation chip) technique
- Allows isolation and cultivation of previously unculturable microorganisms using a multichannel device with miniature diffusion chambers
- Enables growth of microorganisms in their natural environment, increasing likelihood of discovering novel antimicrobial compounds from untapped sources (soil, marine sediments, or extreme environments)
- and approaches
- Genomics analyzes bacterial genomes to identify potential antimicrobial targets and predict resistance mechanisms
- enables exploration of genetic material from environmental samples, uncovering novel antimicrobial compounds and resistance genes from unculturable microorganisms
Alternative sources for antimicrobials
- Marine environments
- Oceans cover more than 70% of Earth's surface and harbor vast diversity of microorganisms that have evolved unique metabolic pathways and produce novel bioactive compounds
- Marine-derived antimicrobials include (inhibit bacterial DNA gyrase) and (inhibit protein synthesis)
-
- Involves systematic combination of chemical building blocks to create large libraries of compounds using solid-phase synthesis and split-and-mix techniques
- Enables rapid generation of diverse chemical structures, increasing chances of discovering novel antimicrobial compounds with desired properties (improved potency, selectivity, or pharmacokinetics)
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- Derived from plants, microorganisms, and other living organisms, natural products have been a rich source of antimicrobial compounds throughout history
- Modern techniques, including , can enhance the production and modification of natural products to create new antimicrobial agents
Strategies against antimicrobial resistance
- Resistance inhibitors
- Compounds target bacterial resistance mechanisms such as (block activity preventing expulsion of antimicrobials from bacterial cells) and (inactivate enzymes restoring effectiveness of β-lactam antibiotics)
- Examples include efflux pump inhibitors () and (, )
- Virulence factor blockers
- Compounds interfere with bacterial virulence factors (molecules or structures enabling bacteria to cause disease) such as , toxins, and secretion systems
- Blocking virulence factors reduces bacterial pathogenicity without directly killing bacteria, offering advantages of reduced selective pressure for resistance development and preservation of beneficial microbiota
- Examples include inhibitors of quorum sensing (), type III secretion systems (), and bacterial adhesion ()
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- Involves identifying new antimicrobial applications for existing drugs, potentially offering faster and more cost-effective solutions to combat
Key Terms to Review (28)
Abyssomicins: Abyssomicins are a class of naturally occurring antibiotics produced by certain bacteria found in deep-sea environments. They have garnered significant attention in the field of antimicrobial discovery due to their potent and diverse antimicrobial properties.
Adhesins: Adhesins are surface structures on pathogens that allow them to adhere to host cells. They play a crucial role in the initial stages of microbial infection.
Adhesins: Adhesins are specialized surface molecules found on the cells of many pathogens that enable them to attach to and infect host cells. They act as the 'sticky' components that facilitate the initial stages of pathogenesis by allowing the pathogen to bind to and invade the host's tissues.
Antibiotic Resistance: Antibiotic resistance is the ability of bacteria and other microorganisms to withstand the effects of antibiotics, rendering these drugs ineffective in treating infections. This phenomenon is a growing global health concern that has significant implications across various aspects of microbiology, including prokaryote habitats, antimicrobial discovery and chemotherapy, and the treatment of bacterial infections.
Brominated Furanones: Brominated furanones are a class of naturally occurring organic compounds that have been identified as potential antimicrobial agents. They are characterized by the presence of a furan ring structure with one or more bromine atoms attached, which gives them unique chemical properties and biological activities.
Clavulanic acid: Clavulanic acid is a beta-lactamase inhibitor that enhances the effectiveness of beta-lactam antibiotics. It is often combined with penicillins to overcome bacterial resistance.
Clavulanic acid: Clavulanic acid is a beta-lactamase inhibitor that is commonly used in combination with certain antibiotics to enhance their effectiveness against resistant bacterial infections. It works by inhibiting the activity of beta-lactamase enzymes produced by bacteria, which can break down and inactivate beta-lactam antibiotics.
Combinatorial Chemistry: Combinatorial chemistry is a powerful approach used in the discovery and development of new antimicrobial agents. It involves the rapid synthesis and screening of large libraries of chemically diverse compounds, allowing researchers to explore a vast chemical space in search of potential drug candidates.
Drug Repurposing: Drug repurposing, also known as drug repositioning, is the process of identifying new therapeutic uses for existing drugs that were originally developed to treat a different disease or condition. This strategy has become an increasingly important approach in antimicrobial discovery, as it can accelerate the development of new treatments by leveraging the safety and pharmacological data already available for approved drugs.
Efflux pumps: Efflux pumps are membrane proteins that actively export harmful substances out of microbial cells, contributing to antibiotic resistance. They play a crucial role in maintaining cellular homeostasis by removing toxic compounds.
Efflux Pumps: Efflux pumps are specialized transport systems found in the cell membranes of bacteria and other microorganisms that actively expel harmful substances, such as antibiotics and toxins, out of the cell. These pumps play a crucial role in the development of antimicrobial resistance and the virulence of bacterial pathogens.
Genomics: Genomics is the study of the entirety of an organism's genes, known as its genome. It involves sequencing, analyzing, and comparing genomes to understand genetic structure and function.
Genomics: Genomics is the comprehensive study of the entire genome, which encompasses the complete set of genetic information within an organism. It involves the analysis of the structure, function, and evolution of genomes, providing insights into the fundamental mechanisms of life and enabling advancements in various fields, including medicine, biotechnology, and evolutionary biology.
High-Throughput Screening: High-throughput screening (HTS) is a method used in drug discovery and genetic engineering to rapidly test a large number of chemical compounds or genetic samples to identify those with a desired biological activity. It is a powerful tool that enables the efficient exploration of vast chemical libraries and genomic data to uncover potential therapeutic agents or identify gene functions.
High-throughput screening methods: High-throughput screening methods are automated techniques used to quickly assess the biological activity of a large number of compounds against specific targets. These methods are crucial for discovering new antimicrobial agents.
IChip: The iChip is a device used in the current strategies for antimicrobial discovery. It allows for the cultivation of previously unculturable microorganisms, providing a novel approach to identifying new antimicrobial compounds from natural sources.
Mannosides: Mannosides are a class of glycosides, which are chemical compounds consisting of a sugar molecule (in this case, mannose) bonded to another molecule. Mannosides are particularly relevant in the context of current strategies for antimicrobial discovery, as they can play a role in targeting and disrupting microbial cell functions.
Marinopyrroles: Marinopyrroles are a class of natural products isolated from marine organisms, such as bacteria and fungi, that have demonstrated potent antimicrobial properties. These compounds have gained attention in the field of antimicrobial discovery as they represent a promising source of novel therapeutic agents.
Metagenomics: Metagenomics is the study of genetic material recovered directly from environmental samples. It enables the analysis of microbial communities without the need for culturing.
Metagenomics: Metagenomics is the study of genetic material recovered directly from environmental samples, bypassing the need for culturing individual microorganisms. It provides a powerful approach for understanding the collective genetic makeup and metabolic potential of complex microbial communities in their natural habitats, with applications in fields such as whole genome methods and pharmaceutical discovery.
Natural Products: Natural products refer to chemical compounds derived from living organisms, such as plants, microorganisms, and animals. These compounds are often used as starting points for the development of new drugs, antimicrobial agents, and other bioactive substances in the context of current strategies for antimicrobial discovery.
Phenylalanine-arginine β-naphthylamide: Phenylalanine-arginine β-naphthylamide is a synthetic compound that has been used as a tool in the field of antimicrobial discovery. It is a chromogenic substrate that can be used to detect the presence of specific enzymes, particularly those involved in bacterial pathogenesis and virulence.
Salicylidene acylhydrazides: Salicylidene acylhydrazides are a class of organic compounds that have shown promise as antimicrobial agents, particularly in the context of current strategies for antimicrobial discovery. These compounds consist of a salicylidene (a salicylaldehyde derivative) coupled with an acylhydrazide functional group, giving them a unique structure that can interact with and inhibit various microbial targets.
Synthetic Biology: Synthetic biology is an interdisciplinary field that combines principles from biology, engineering, and technology to design and construct novel biological systems, devices, and organisms. It aims to create artificial biological components, networks, and pathways that do not exist in nature, with the goal of expanding our understanding and capabilities in areas such as antimicrobial discovery.
Tazobactam: Tazobactam is a beta-lactamase inhibitor that is often combined with certain antibiotics, such as piperacillin, to enhance their effectiveness against a broader spectrum of bacteria. It works by inhibiting bacterial enzymes called beta-lactamases, which can degrade and inactivate certain antibiotics, thereby improving the antibiotic's ability to kill the target bacteria.
Teixobactin: Teixobactin is a novel antibiotic discovered in 2015 that shows effectiveness against Gram-positive bacteria by binding to lipid II and lipid III, crucial components in cell wall synthesis. It is noted for its potential to combat antibiotic-resistant bacteria.
β-lactamase inhibitors: β-lactamase inhibitors are compounds that block the activity of β-lactamase enzymes, which are produced by bacteria to resist β-lactam antibiotics. They are often combined with β-lactam antibiotics to enhance their effectiveness against resistant bacterial strains.
β-Lactamases: β-Lactamases are enzymes produced by bacteria that confer resistance to β-lactam antibiotics, such as penicillins and cephalosporins, by hydrolyzing the β-lactam ring, which is essential for the antibiotics' mechanism of action. These enzymes are a key mechanism of antimicrobial resistance and a major challenge in the discovery of new antibiotics.