Chemotherapeutic Agents and Antibiotics Targeting Microbial Pathogenesis

Introduction

Microbial pathogenesis refers to the process by which microorganisms cause disease in a host.

Chemotherapeutic agents and antibiotics are chemical substances used to inhibit or kill these pathogens without harming host cells.
Chemotherapeutic Agents

These are synthetic or semi-synthetic compounds used to treat microbial infections.

Example: Sulfonamides, quinolones, isoniazid, and antitubercular drugs.

They act by inhibiting specific microbial metabolic pathways essential for growth or survival.

1. Chemotherapy and Drug Resistance Chemotherapeutic agents and antibiotics. Modes of action of antibiotics on microorganisms Amjad Khan Afridi Lecturer, Department of Health & Biological Sciences Abasyn University Peshawar Chapter #03

2. Chemotherapy is a drug treatment that uses powerful chemicals to kill fast- growing cells in the body. Chemotherapy resistance occurs when cancers that have been responding to a therapy suddenly begin to grow . In other words, the cancer cells are resisting the effects of the chemotherapy . You may hear statements like the "cancer chemotherapy failed" . When this occurs, the drugs will need to be changed. Chemotherapy https:// www.cancer.gov/about- cancer/treatment/research/drug-combo- resistance#:~:text=In%20addition%20to%20arising%20through,turn%20genes%20on%20or%20off.

3. Doxorubicin is considered one of the strongest chemotherapy /anticancer drugs for breast cancer . It can kill cancer cells at every point in their life cycle, and it's used to treat a wide variety of cancers , not just breast cancer. Produced by Streptomyces bacteria specially by Streptomyces peucetius . Doxorubicin is also known as “The Red Devil” because it is a clear bright red color .

4. Doxorubicin also called an anthracycline . It stops the growth of cancer cells by blocking an enzyme called topo-isomerase -II . Cancer cells need this enzyme to divide and grow. Anthracycline are among the most e ffective and widely used agents in cancer treatment, but also among the most toxic, particularly to the heart . Anthracyclines are cytotoxic antibiotics that interfere with DNA replication and transcription in cancer cells

5. They are used to treat a wide range of cancers, including: Leukemias ( blood and bone marrow cancer) and lymphomas ( lymphatic system) Breast cancer Sarcomas ( bones and soft tissues) Ovarian and bladder cancers Examples : (Types) Doxorubicin (Adriamycin)- Breast, lung, ovarian, and stomach cancers Daunorubicin- Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Epirubicin- Breast cancer Idarubicin- Lymphoma

6. Anthracyclines work through multiple mechanisms , which makes them highly effective: DNA intercalation – The drug inserts between DNA base pairs, disrupting replication and transcription. Topoisomerase II inhibition – Prevents the enzyme from relaxing supercoiled DNA , leading to double-strand breaks and cell death. Free radical formation – Generates reactive oxygen species (ROS), causing oxidative damage to DNA, proteins, and membranes. Apoptosis induction – Triggers programmed cell death in cancer cells. Mechanism of Action

7. Selective toxicity : A D rug that kills harmful microbes without damaging the host cells Antibacterial spectrum Range of activity of an antibiotic. A broad spectrum Antibiotic that can inhibit wide range of G- positive and G- negative bacteria e.g. Carbapenems, 3- 4th generation cephalosporins, quinolones. A narrow spectrum Antibiotic that is active only against a limited number of bacteria e.g. penicillin G, 1- 2 nd generation cephalosporins, oxazolidone . Terminologies

8. Effects of Combinations of Drugs Synergism occurs when the effect of two drugs together is greater than the effect of either alone. Antagonism occurs when the effect of two drugs together is less than the effect of either alone.

9. Effects of Combinations of Drugs

10. Antibiotic/Antimicrobial Antibiotic : Chemical produced by a microorganism that kills or inhibits the growth of another microorganism Antimicrobial agent : Chemical that kills or inhibits the growth of microorganisms

11. Antimicrobial Agents Disinfectant: Antimicrobial agent used only on inanimate objects Chemotherapeutic agent: Antimicrobial agent that can be used internally Bactericidal: Agent that kills bacteria Bacteriostatic: Agent that inhibits the growth of bacteria

12. II.HISTORY 7 1929 Penicillin discovered by Alexander Fleming 1940 Florey and Chain mass produce penicillin for war time use, becomes available to the public. 1935 Sulfa (sulfonamide- prontosil rubrum) drugs discovered by Gerhard Domagk in 1935. 1943 Streptomycin ( aminoglycoside drugs) discovered by Selman Waksman .

13. Mechanisms of Antimicrobial Action Bacteria have their own enzymes for √ Cell wall formation √ Protein synthesis √ DNA replication √ RNA synthesis √ Synthesis of essential metabolites

14. Modes of Antimicrobial Action

15. Basic mechanisms of antibiotics

16. Inhibition of cell wall synthesis – Penicillins and cephalosporins stop synthesis of cell wall by preventing cross linking of peptidoglycan units . – Bacitracin and vancomycin also interfere here. – Excellent selective toxicity 13

17. The bacterial cell membrane is also called cytoplasmic membrane . Its main compounds are proteins and lipids. Polymyxins can selectively combine with phosphatide in the cell membrane and cause the increase of membranous permeability . As the result, some important materials will outflow from bacterial cells and result in death of bacteria. Inhibition of functions of cellular membrane

18. Acting on DNA replication Quinolones Ciprofloxacin Metronidazole Quinolones Fluoroquinolones Inhibition of nucleic acid synthesis Acting on RNA Rifampin Rifabutin

19. Due to differences in ribosomes Eucaryotic cells have 80S (60S + 40S subunits) ribosomes. Procaryotic cells have 70S (50S + 30S subunits) ribosomes. Examples: Chloramphenicol , Macrolides and Clindamycin bind to the 50S subunit. Tetracyclines and Aminoglycosides bind to the 30S subunit. 16 Inhibition of protein synthesis

20. Sulfonamides Dapsone Trimethoprim Para Aminosalicylic acid Antimetabolites

21. Drug resistance is simply defined as the ability of disease- causing microorganisms to continue multiplying despite the presence of drugs that usually kill them . When the bacteria show resistance to one drug, they are also resistant to some other drugs. This phenomenon is called cross drug resistance . 18 Resistance To Anti Bacterial Agents

22. Inhibition of drug uptake or blocking the entry ( Change their cell membrane and cell wall permeability to the drug ) Produce enzymes that destroy the chemical structures of drugs Alter or modified the target molecule. Activation of drug efflux pump. Active efflux is a common resistance mechanism in a wide range of bacterial pathogens . It is responsible for the transport of such toxic compounds as drugs, toxins, and detergents. Mechanisms of Antibacterial Resistance

23. Have highly selective toxicity to the pathogenic Microorganisms in host body Have no or less toxicity to the host. Low propensity for development of resistance. Not induce hypersensitive in the host. Have rapid and extensive tissue distribution Be free of interactions with other drugs. Be relatively in expensive Ideal Antimicrobial Drug

24. Prevention of Antibiotic Resistance Patients : Take antibiotics exactly as the doctor prescribes. Do not skip doses. Complete the prescribed course, even when you feeling better. Only take antibiotics prescribed for you. Do not save antibiotics for the next illness. Discard any leftover medication once the treatment is completed. Do not ask for antibiotics to your doctor. Prevent infections by practicing hygiene and recommended vaccines. Health professionals: Prescribe antibiotics only when they are absolutely necessary – giving them at the right dose and only for as long as they areneeded. Avoid unnecessary overlaps in antibiotics. Become familiar with resistance trends in your region.

25. Minimal Inhibitory Concentration

26. Thank You

27. https://www.youtube.com/watch?v=Cj9UADDIidI&ab_channel=AlilaMedicalMedia https://www.youtube.com/watch?v=3Y1fLj5SQMU&ab_channel=AnimatedbiologyWith arpan https://www.youtube.com/watch?v=N7dTM7nLw1Q&ab_channel=Henrik%27sLab https://www.youtube.com/watch?v=8VZH4GZLWZc&ab_channel=AlilaMedicalMedia https://www.youtube.com/watch?v=8VZH4GZLWZc&ab_channel=AlilaMedicalMedia https://www.youtube.com/watch?v=NGwP471sehI&ab_channel=StrongMedicine