Antimicrobial drug discovery Flashcards
Explain the drug discovery process
arget identification: The first step in the drug discovery process is to identify a specific target in the body that is involved in the disease process. This target could be a protein, enzyme, receptor, or other molecule that plays a role in the disease.
Lead identification: Once a target is identified, the next step is to find a lead compound that can interact with the target and potentially provide therapeutic benefit. This involves screening large libraries of molecules to find compounds that have the desired activity against the target.
Lead optimization: After a lead compound is identified, it undergoes a process of optimization to improve its potency, selectivity, and other properties that affect its ability to become a viable drug candidate. This involves making structural modifications to the compound and testing its effects in vitro and in vivo.
Preclinical testing: Once a lead compound has been optimized, it undergoes preclinical testing in animal models to evaluate its safety, pharmacokinetics, and efficacy in treating the disease. This stage helps to identify any potential toxicities or side effects of the drug.
Clinical trials: If a drug candidate passes preclinical testing, it moves on to clinical trials, which involve testing the drug in humans. Clinical trials are conducted in three phases, each of which involves testing the drug in increasingly larger groups of people to evaluate its safety, efficacy, and optimal dosing.
Challenges of antimicrobial drug discovery
Resistance: One of the biggest challenges in antimicrobial drug discovery is the development of resistance by microorganisms. Bacteria, viruses, fungi, and other pathogens can rapidly evolve and develop resistance to existing antimicrobial drugs. This means that new drugs need to be constantly developed to keep up with the evolving resistance patterns of pathogens.
Limited targets: Unlike other disease areas, such as cancer or cardiovascular disease, antimicrobial drug discovery is limited in terms of targets. There are only a few types of microorganisms that cause the majority of infectious diseases, and many of these microorganisms share common characteristics, which can make it difficult to develop drugs that are selective for a particular target.
Toxicity: Many antimicrobial drugs have toxic side effects, which can limit their use. For example, some antibiotics can cause damage to the liver or kidneys, while antiviral drugs can cause neurological side effects.
Cost: Antimicrobial drug discovery is expensive and time-consuming. The cost of developing a new drug can run into the hundreds of millions of dollars, and the process can take many years. This can make it difficult for small biotech companies to enter the market and compete with larger pharmaceutical companies.
Regulatory challenges: The regulatory environment for antimicrobial drug discovery is complex and constantly evolving. In recent years, there has been increased scrutiny by regulatory agencies on the use of antibiotics in livestock and agriculture, which has led to increased pressure on pharmaceutical companies to develop new antimicrobial drugs that are more selective and have fewer side effects.
Limited financial incentives: Finally, there are limited financial incentives for pharmaceutical companies to invest in antimicrobial drug discovery. Unlike other areas of drug development, such as cancer or chronic diseases, there is a relatively small market for antimicrobial drugs, which means that there is less potential for profit. This has led to a decrease in the number of companies investing in antimicrobial drug discovery in recent years.
explain barriers to entry in gram negative bacteria
Outer membrane: The outer membrane of gram-negative bacteria provides a physical barrier that can prevent drugs from penetrating the cell.
Efflux pumps: Gram-negative bacteria have efflux pumps that can actively pump drugs out of the cell, reducing their effectiveness.
Porins: The porins in the outer membrane of gram-negative bacteria are selective channels that allow certain molecules to pass through. The size and charge of the porin can limit the entry of certain drugs.
Enzymatic degradation: Gram-negative bacteria produce enzymes, such as beta-lactamases, that can degrade certain classes of drugs, reducing their effectiveness.
Limited drug targets: There are fewer validated drug targets in gram-negative bacteria compared to gram-positive bacteria, making it more difficult to identify new drugs.
Limited drug permeability: Even if a drug is able to penetrate the outer membrane of a gram-negative bacterium, it may have difficulty crossing the inner membrane due to the hydrophilic nature of the periplasmic space.
Complex signaling networks: Gram-negative bacteria have complex signaling networks that can allow them to sense and respond to changes in their environment, making it more difficult to target them with drugs.
What is a good antibacterial target
Essentiality: The target should play a critical role in the bacterial cell, such as a key metabolic pathway or an essential enzyme, that is necessary for the survival or growth of the bacterium.
Selectivity: The target should be specific to the bacteria and not present in or significantly different from human cells, to minimize off-target effects and toxicity to the host.
Conservation: The target should be conserved across a range of bacterial strains, so that a drug targeting the target can be effective against multiple bacterial infections.
Druggability: The target should be amenable to small molecule drug development, meaning it can be inhibited by a small molecule drug with reasonable binding affinity and specificity.
Resistance: The target should be relatively conserved, but not so highly conserved that mutations in the target can easily confer drug resistance.
Examples of good antibacterial targets include:
Bacterial cell wall synthesis enzymes, such as penicillin-binding proteins (PBPs) and Mur enzymes, that are essential for the growth and survival of bacteria but not present in human cells.
Bacterial protein synthesis machinery, such as the ribosome or aminoacyl-tRNA synthetases, that are essential for bacterial growth but differ significantly from their human counterparts.
Essential bacterial metabolic pathways, such as folate biosynthesis or the tricarboxylic acid (TCA) cycle, that are absent or significantly different in human cells.
Explain gram negative membrane penetration
