Antibiotics have revolutionized modern medicine, saving countless lives by combatting bacterial infections. However, the emergence of antibiotic-resistant bacteria presents a formidable challenge to global health. Pharmacogenetics focuses on the interplay between an individual's genetic makeup and their response to drugs. This presentation delves into the intriguing realm of pharmacogenetics within the context of antibiotic therapy, aiming to shed light on how genetic variations can influence antibiotic effectiveness and how this knowledge can be harnessed to develop more precise, personalized treatment strategies.

1. PHARMACOGENETICS OF
ANTIBIOTIC DRUGS
Gunjit Setia

2. CONTENTS
• Introduction
• Pharmacogenetics basics
• Antibiotic drugs
• Mechanism of action of antibiotic drugs
• Antibiotic resistance
• The Indian Scenario
• Approved antibiotics & its resistance
• Mechanisms involved in inter-individual variability in drug-response
• Major CYP enzymes in human drug metabolism (liver & intestine)
• Drug metabolised by genes
• Genetic variation
• Genetic variation affect drug effect
• Tuberculosis: mycobacterium tuberculosis (NAT2 gene)
• Pharmacogenetics: anti-mycobacterial agent
• Macrolides metabolism
• Pharmacogenetics: macrolides
• GWAS Case study
• Conclusion
• References

3. INTRODUCTION
Antibiotics have revolutionized modern medicine, saving countless
lives by combatting bacterial infections.
• However, the emergence of antibiotic-resistant bacteria presents a
formidable challenge to global health.
Pharmacogenetics focuses on the interplay between an individual's
genetic makeup and their response to drugs.
This presentation delves into the intriguing realm of pharmacogenetics
within the context of antibiotic therapy, aiming to shed light on how
genetic variations can influence antibiotic effectiveness and how this
knowledge can be harnessed to develop more precise, personalized
treatment strategies.

4. PHARMACOGENETICS
The study of how an individual's genetic makeup
influences their response to drugs.
Key Concepts
Genetic
Variation Drug
Metabolism
Efficacy and
Safety
Our genes can vary
significantly between
individuals, leading to
diverse drug
responses.
Genetic variations can
impact how the body
processes and
metabolizes drugs.
Pharmacogenetics
can predict drug
efficacy and
potential adverse
effects.

5. ANTIBIOTIC DRUGS
PENICILLIN CEPHALOSPORINS FLUOROQUINOLONES AMINOGLYCOSIDES MONOBACTAMS CARBAPENEMS MACROLIDES
Natural First generation Ciprofloxacin (Cipro) Amikacin Aztreonam Ertapenem Azithromycin
Penicillin G Cephalothin Levofloxacin (Levaguin) Gentamicin Imienem Clarithromycin
Penicillin-VK Cefazolin (Ancef, Kefzol) Moxifloxacin (Avelox) Kanamycin Meropenem Dirithromycin
Cephapririn Norfloxacin Neomycin Erythromycin
Cephalexin (Keflex) Tobramycin Clindamycin
Other
Penicillinase
Resistant Second Generation
Methicillin Cefacor
Nafcillin Cefotetan (Cefotan)
Oxacillin Other
other
Aminopenicillins Third Generation
Ampicillin Ceftriaxone (Rocephin)
Other
Fourth Generation
Cefpirome
Cefepime
https://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism

6. MECHANISM
OF ACTION
OF
ANTIBIOTIC
DRUGS
Drug Mechanism of action
Rifampin:
Most effective against intracellular
phagocytized Staphylococcus aureus in
macrophages
Linezolid:
Binds to the 23S portion of the 50S subunit
and acts by preventing the formation of
the initiation complex between
the the 30S and 50S subunits of the ribosome
https://www.orthobullets.com/basic-science/9059/antibiotic-classification-and-mechanism
(Penicillins,
Vancomycin)
(Cephalosporins)
(Fluoroquinolones
)
(Aminoglycosides)

7. ANTIBIOTIC RESISTANCE
• Resistance occurs when bacteria and other microorganisms develop mechanisms to withstand the effects of
antibiotics.
• According to the World Health Organization (WHO)
• Antibiotic resistance is one of the most significant threats to global health, food security, and development.
• Antibiotic resistance occurs naturally, but misuse of antibiotics in humans and animals is accelerating the
process.
• A growing number of infections – such as pneumonia, tuberculosis, gonorrhoea, and salmonellosis – are
becoming harder to treat as the antibiotics used to treat them become less effective
• Centers for Disease Control and Prevention (CDC)
indicates that at least 2.8 million people are infected
with antibiotic-resistant bacteria in the United States
each year, leading to over 35,000 deaths.

8. THE INDIAN SCENARIO
• In India, 700,000 people die every year from drug-resistant strains
of common bacterial infections, HIV, TB and malaria.
• Nearly 200,000 people die every year from multidrug-resistant and
extremely drug-resistant tuberculosis (TB) alone ~ WHO,2016.
• Antibiotic-resistant neonatal infections cause the deaths of nearly
60,000 new-borns each year.
Source From: https://amr-
review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf

9. Approved
Antibiotics & its
Resistance
Source From: https://www.cdc.gov/drugresistance/biggest-threats.html

10. MECHANISMS INVOLVED IN INTER-
INDIVIDUAL VARIABILITY IN DRUG-RESPONSE
https://www.cambridge.org/core/books/abs/anesthetic-pharmacology/principles-of-drug-
biotransformation/1D62EE98AD50DA813F75FAD76F6B58A3

11. MAJOR CYP ENZYMES IN HUMAN DRUG
METABOLISM (LIVER & INTESTINE)

12. MAJOR CYP ENZYMES IN HUMAN DRUG
METABOLISM (LIVER & INTESTINE)

13. Drug Metabolized by Genes

14. GENETIC VARIATION
• A variation in the DNA sequence that is
present at an allele frequency of 1% or greater
in a population.
• This variation is fundamental to evolution and
plays a crucial role in determining an
individual's traits, susceptibility to diseases,
and responses to drugs, including antibiotics.
Gene Variation
Variation
SNP INDELs

15. GENETIC VARIATION AFFECT DRUG
EFFECT

16. GENETIC VARIATION AFFECT DRUG
EFFECT

17. GENETIC VARIATION AFFECT DRUG
EFFECT

19. PHARMACOGENETICS: ANTI-MYCOBACTERIALAGENT
ATT-DILI
(Anti-tuberculosis
treatment drug-
induced liver injury)

20. Source From: https://www.pharmgkb.org/pathway/PA166160731

21. Pharmacogenetics: Macrolides

23. Source from: https://europepmc.org/article/med/33841421#free-full-text

25. CONCLUSION
• Genes directly or indirectly regulate the metabolism of Antibiotic drugs and vice versa. Genetic Variation in a
genes results in dysregulation of antibiotics and affect the effect of drug on its target bacteria or other
organism. Pharmacogenetics plays a vital role in development of specific drugs that will not harm the
individual.
• Nowadays, various GWAS studies are being conducted within a group of population for enhancement of new
drug strategies and pathways.

26. REFERENCES
• Stocco G, Lucafò M, Decorti G. Pharmacogenomics of Antibiotics. Int J Mol Sci. 2020;21(17):5975. Published 2020 Aug 19. doi:10.3390/ijms21175975
• Roden DM, Wilke RA, Kroemer HK, Stein CM. Pharmacogenomics: the genetics of variable drug responses. Circulation. 2011;123(15):1661-1670. doi:10.1161/CIRCULATIONAHA.109.914820
• Hemanth Kumar AK, Ramesh K, Kannan T, et al. N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis. Indian J Med Res. 2017;145(1):118-123.
doi:10.4103/ijmr.IJMR_2013_15
• Klein DJ, Boukouvala S, McDonagh EM, et al. PharmGKB summary: isoniazid pathway, pharmacokinetics. Pharmacogenet Genomics. 2016;26(9):436-444. doi:10.1097/FPC.0000000000000232
• Kharasch ED. Principles of drug biotransformation. In: Evers AS, Maze M, Kharasch ED, eds. Anesthetic Pharmacology: Basic Principles and Clinical Practice. 2nd ed. Cambridge: Cambridge
University Press; 2011:72-89. doi:10.1017/CBO9780511781933.007
• Review on AMR, Antimicrobial resistance: Tackling a crisis for the health and wealth of nations, 2014.
• WHO, Tuberculosis Factsheet, Online, Available at: http://www.who.int/mediacentre/ factsheets/fs104/en/
• Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, et al. Antibiotic resistance – the need for global solutions, The Lancet Infectious Diseases 2013; 13: p.1057-98.
• Zhao M, Ma J, Li M, et al. Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int J Mol Sci. 2021;22(23):12808. Published 2021 Nov 26. doi:10.3390/ijms222312808
• Di X, Bai N, Zhang X, et al. A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity. Braz J Infect Dis. 2015;19(4):339-349.
doi:10.1016/j.bjid.2015.03.006
• Li J, Zhang Y, Jilg AL, et al. Variants at the MHC Region Associate With Susceptibility to <i>Clostridioides difficile</i> Infection: A Genome-Wide Association Study Using Comprehensive
Electronic Health Records. Frontiers in Immunology. 2021;12:638913. DOI: 10.3389/fimmu.2021.638913. PMID: 33841421; PMCID: PMC8026859.
• Naz S, Paritosh K, Sanyal P, et al. GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis. Elife. 2023;12:e75860.
Published 2023 Jan 25. doi:10.7554/eLife.75860

27. LINKS TO DATABASE REFERRED
• https://www.futuremedicine.com/doi/10.2217/pgs-2018-0142
• https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Human/ema_group_t
ypes/ema_medicine?search_api_views_fulltext=antibiotic.
• https://www.dreamstime.com/illustration/mechanism-antibiotics.html
• https://www.pharmgkb.org/pathway/PA166160731
• https://www.pharmgkb.org/pathway/PA166151813
• https://www.pharmgkb.org/pathway/PA166254101
• https://www.pharmgkb.org/search?query=Beta-lactamase&type=Pathway
• https://www.genome.jp/kegg/pathway.html
• https://go.drugbank.com/drugs/DB01053
• https://platform.opentargets.org/drug/CHEMBL370143
• https://genetics.opentargets.org/study/SAIGE_960
• https://genetics.opentargets.org/gene/ENSG00000159788
• https://pheweb.org/UKB-TOPMed/pheno/960.2