This document discusses mechanisms of antibiotic resistance in bacteria. It describes intrinsic resistance that is natural to certain organisms and acquired resistance that develops through genetic mutations or transfer of resistance genes. The mechanisms include modifications or destruction of antibiotics by enzymes, decreased antibiotic penetration through reduced permeability or efflux pumps, changes to antibiotic target sites, and global adaptive responses in bacterial cells.
This document discusses mechanisms of antibiotic resistance in bacteria. It describes intrinsic resistance that is natural to certain organisms and acquired resistance that develops through genetic mutations or transfer of resistance genes. The mechanisms include modifications or destruction of antibiotics by enzymes, decreased antibiotic penetration through reduced permeability or efflux pumps, changes to antibiotic target sites, and global adaptive responses in bacterial cells.
This document discusses mechanisms of antibiotic resistance in bacteria. It describes intrinsic resistance that is natural to certain organisms and acquired resistance that develops through genetic mutations or transfer of resistance genes. The mechanisms include modifications or destruction of antibiotics by enzymes, decreased antibiotic penetration through reduced permeability or efflux pumps, changes to antibiotic target sites, and global adaptive responses in bacterial cells.
This document discusses mechanisms of antibiotic resistance in bacteria. It describes intrinsic resistance that is natural to certain organisms and acquired resistance that develops through genetic mutations or transfer of resistance genes. The mechanisms include modifications or destruction of antibiotics by enzymes, decreased antibiotic penetration through reduced permeability or efflux pumps, changes to antibiotic target sites, and global adaptive responses in bacterial cells.
REG. NO : 17mslsmm20 CENTRE : HUMAN GENETICS & MOLECULAR MEDICINE CENTRAL UNIVERSITY OF PUNJAB INTRODUCTION Antibiotics or antibacterials are a type of antimicrobial used in the treatment and prevention of bacterial infection. They may either kill or inhibit the growth of bacteria. The conc. of drug at the site of infection must inhibit the organism and also remain below the level that is toxic to human cells. Antibiotic resistance is defined as microorganisms that are not inhibited by usually achievable systemic conc. of an antimicrobial agent with normal dosage schedule fall in the MIC range. MECHANISM OF ANBIOTIC ACTION
Fig 1: Different mechanisms of antibiotic action
MECHANISM OF ANTIBIOTIC RESISTANCE
Intrinsic Acquired
Genetic Methods
Chromosomal Methods Extrachromosomal Method
INTRINSIC RESISTANCE It is natural. Interaction of many organisms with their environment. Resistance of Mycoplasma species to B-lactams antibiotics, due to lack of cell wall.
Fig 2: Intrinsic resistance
MUTATIONAL RESISTANCE Mutations resulting in antimicrobial resistance alter the antibiotic action via :
I. Modifications of the antimicrobial target.
II. A decrease in the drug uptake.
III. Activation of efflux mechanisms to extrude the harmful
molecule.
IV. Global changes in important metabolic pathways via modulation
of regulatory networks. EXTRACHROMOSOMAL METHOD Extrachromosomal method means acquisition of foreign DNA coding for resistance determinants through horizontal gene transfer.
Fig 3: Three main strategies of acquisition of external genetic
material by bacteria. MECHANISTIC BASIS OF ANTIMICROBIAL RESISTANCE
1. Modification of the antimicrobial molecule.
2. Prevention to reach the antibiotic target (by decreasing
penetration or actively extruding the antimicrobial compound)
3. Changes and/or bypass of target sites.
4. Resistance due to global cell adaptive processes.
MODIFICATIONS OF THE ANTIBIOTIC MOLECULE I. Chemical alterations of the antibiotic : Production of enzymes capable of introducing chemical changes to the antimicrobial molecule.
Different types of reactions catalyzed by modifying enzymes are :
II. Destruction of the Antibiotic Molecule : The main mechanism of B-lactam resistance relies on the destruction of this compounds by the action of B-lactamases. This enzymes destroy the amide bond of the B-lactam ring.
Fig 4: Inactivation of penicillin by penicillinase enzyme
DECREASED ANTIBIOTIC PENETRATION AND EFFLUX I. Decreased Permeability :
Fig 5: Decrease permeability of porin channels
II. Efflux Pumps :There are 5 major families of efflux pumps including : a) The major facilitator superfamily (MFS) b) The small multidrug resistance family (SMR) c) The resistance nodulation cell division family (RND) d) The ATP binding cassette family (ABC) e) The multidrug and toxic compound extrusion family (MATE)
Fig 6: Different types of efflux pumps
CHANGES IN TARGET SITES Bacteria have evolved different tactics including i) protection of the target (avoiding the antibiotic to reach its binding site) and ii) modification of the target site that result in decrease affinity for the antibiotic molecule.
Fig 7: Mechanism of target site protection and modification.
RESISTANCE DUE TO GLOBAL CELL ADAPTATIONS Development of resistance to daptomycin (DAP) and vancomycin are the most clinically relevant examples of resistant phenotypes that are the result of a global cell adaptive response to the antibacterial attack. i. DAP is a lipopeptide antibiotic produced by the innate immune system. ii. It exerts its effect by altering cell envelope homeostasis. iii. It complexed with calcium and directed to the CM. iv. It oligomerizes at the outer leaflet of the CM and the oligomers reach the inner CM leaflet. v. They organize and form transmembrane pore like structure and promote leakage of ions from the cytoplasm. Bacteria developed DAP resistance by changing in a three component regulatory system designated LiaFSR.
LiaFSR is composed of three proteins
a. LiaF, is a transmembrane protein that appears to negatively
regulate the system.
b. LiaS, is a classical sensor histidine kinase protein that
phosphorylates the response regulator.
c. LiaR, is the response regulator of the system.
REFERENCES Munita J. M., & Arias, C. A. (2016). Mechanisms of Antibiotic Resistance. Microbiology spectrum, 4(2).
Thomas, C. M., & Nielsen, K. M. (2005). Mechanisms of, and
barriers to, horizontal gene transfer between bacteria. Nature reviews microbiology, 3(9), 711-721.
Wilson, D. N. (2013). Ribosome-targeting antibiotics and
mechanisms of bacterial resistance. Nature Reviews Microbiology, 12(1), nrmicro3155.