It refers to unresponsiveness of a microorganism to an AMA. The concentration of drug at the site of infection must inhibit the organism and also remain below the level that is toxic to human cells.
evolution is mostly aided by poor therapeutic practices by healthcare workers, as well as indiscriminant use of antibiotics for agricultural and animal husbandry purposes. Physicians fail to incorporate the pharmacological properties of antimicrobials amplify the speed of development of drug resistance.
Some microbes have always been resistant to certain AMAs
Others like Strep. pyogenes and spirochetes have not developed significant resistance to penicillin despite its widespread use for> 50 years
If the target is intracellular and the drug requires active transport across the cell membrane, a mutation or phenotypic change that slows or abolishes this transport mechanism can confer resistance.
multidrug and toxic compound extruder (MATe) major facilitator superfamily (MFS) transporters small multidrug resistance (SMR) system resistance nodulation division (RND) exporters ATP binding cassette (ABC) transporters
Efflux pumps are a prominent mechanism of resistance for parasites, bacteria, and fungi. specifically chloroquine, quinine, mefloquine, halofantrine, lumefantrine, and the artemether-lumefantrine combination Drug resistance to most antimalarial drugs is mediated by an ABC transporter encoded by Plasmodium falciparum multidrug resistance gene 1 (Pfmdr1)
B-lactamases are produced by staphylococci, Haemophilus, gonococci, etc. which inactivate penicillin G.
, despite the total population being considered susceptible on testing. In bacteria vancomycin in S. aureus, vancomycin in Enterococcus faecium ; rifampin, isoniazid, and streptomycin in M. tuberculosis, and penicillin in S. pneumoniae. In fungi fluconazole in Cryptococcus neoformans & Candida albicans . Drug dependence in bacteria : An uncommon situation, where an organism not only becomes resistant to an AMAs but starts requiring it for growth Enterococcus, which easily develops vancomycin resistance, can, after prolonged exposure to the antibiotic, develop vancomycin-requiring strains.
Nucleoside reverse transcriptase inhibitors such as zidovudine are 2′-deoxyribonucleoside analogs that are converted to their 5′-triphosphate form and compete with natural nucleotides
Clinically meaningful resistance occurs when there is a single point mutation in the DHPSgene accompanied by at least a double mutation in the DHFR gene. M. tuberculosis katGSer315 mutations - resistance to isoniazid; the M814V mutation in the reverse transcriptase gene of HIV-1, causing resistance to lamivudine; a cytochrome-b gene mutation causing resistance to the antimalaria drug atovaquone; and Candida albicans fks1 Ser645 mutations causing resistance to echinocandins.
The ability to protect genetic information from disintegrating and also to be flexible enough to allow genetic changes that lead to adaptation to the environment is essential to all living things development of a defect in one of these repair mechanisms leads to a high degree of mutations in many genes; such isolates are termed
acyl-homoserine lactones (AHLs) Autoinducing peptide (AIP) Proved to be very potent method for bacterial virulence inhibition. QS inhibitors have shown to be potent virulence inhibitor both in in-vitro and in-vivo,using infection animal models. Gram-negative pathogens control virulence factor production using LuxI/LuxR-type QS circuits
Plasmids, insertion sequences and transposons are important for resistance
Transduction- DNA includes a gene for drug resistance, the newly infected bacterial cell may acquire resistance transfer of antibiotic resistance - strains of S. aureus. .
Enterococci - host-range conjugative plasmids that are involved in the transfer and spread of resistance genes among gram-positive organisms Chloramphenicol resistance of typhoid bacilli, streptomycin resistance of E. coli, penicillin resistance of Haemophilus and gonococci
Plasmids r Extra chromosomal genetic elements can replicate independently and freely in cytoplasm. Plasmids which carry genes resistant ( r-genes) are called R-plasmids. The donor plasmid containing the Transposons, co-integrate with acceptor plasmid & undergoes cross linking Both plasmids then separate and each contains the r-gene carrying the transposon.
broad-spectrum drugs should be used only when a specific one cannot be determined or is not suitable Infection by organisms notorious for developing resistance, e.g. Staph. aureus, E. coli, M. tuberculosis, Proteus, etc. must be treated intensively
Antimicrobial resistance mechanism
- Dr Mangala Nischal
• Natural Resistance
• Acquired Resistance
• Resistance Mechanisms
- Gene Transfer
• Cross Resistance
• Prevention of Drug Resistance
• WHO - Defines as micro-organisms that are not inhibited by usually
achievable systemic concentration of an antimicrobial agent(AMA)
with normal dosage schedule and / or fall in the minimum inhibitory
concentration (MIC) range.
• when a species is subjected to chemical warfare, that threatens its
extinction it often evolves mechanisms to survive under that stress
development of resistance.
• Two major factors are associated with emergence of antibiotic
- Clinical/ Environmental practices.
NATURAL RESISTANCE :-
• Some microbes lack the metabolic process or the target site for
• e.g: - Gram-negative bacilli are normally unaffected by penicillin G
- M. tuberculosis is insensitive to tetracyclines.
• This resistance does not pose a significant clinical problem.
ACQUIRED RESISTANCE :-
• It is the development of resistance by an organism (which was
sensitive before) due to the prolonged use of an AMA.
• Some bacteria are notorious for rapid acquisition of resistance
e.g. staphylococci, coliforms, tubercle bacilli.
RESISTANCE MECHANISMS :-
BIOCHEMICAL MECHANISMS -
• Antimicrobial resistance can develop at any one or more of steps in
• Reduced entry of antibiotic into pathogen
• Enhanced export of antibiotic by efflux pumps
• Release of microbial enzymes that destroy the antibiotic
• Alteration of microbial proteins that transform pro-drugs to the
• Alteration of target proteins
• Development of alternative pathways to those inhibited by the
Reduced Entry of Drug into Pathogen :-
• Small polar molecules & antibiotics, enter the cell through protein
channels called Porins.
• Absence of, mutation in, or loss of a favored porin channel can slow
the rate of drug entry into a cell or prevent entry altogether
reducing drug concentration at the target site.
• If target is intracellular mutation or phenotypic change that slows
or abolishes this transport mechanism resistance.
Resistance Due to Reduced Affinity of Drug to Altered Target Structure :-
• A reduced affinity of drug for its target or the enzyme that converts the
prodrug to active drug. Such alterations may be due to
Mutation of the natural target (e.g., fluoroquinolone resistance)
Target modification (e.g., ribosomal protection type of resistance to
macrolides and tetracyclines)
Acquisition of a resistant form of the native, susceptible target (e.g.,
staphylococcal methicillin resistance caused by production of a low-affinity
• Examples :-
• The penicillin-resistant gonococci are less permeable to penicillin G.
• Chloroquine-resistant P. Falciparum accumulates less chloroquine.
Resistance Due to Drug Efflux :-
• Microorganisms can overexpress efflux pumps and then expel
antibiotics to which their susceptible.
• Five major systems of efflux pumps
- The multidrug and toxic compound extruder (MATE)
- The major facilitator superfamily (MFS) transporters
- The small multidrug resistance (SMR) system
- The resistance nodulation division (RND) exporters
- ATP binding cassette (ABC) transporters
• Drug resistance to erythromycin, fluoroquinolones & Anti-malarial
drugs are mediated through these Efflux pumps.
Resistance Due to Destruction of Antibiotic :-
• Drug inactivation is a common mechanism of drug resistance.
• Bacterial resistance to aminoglycosides aminoglycoside-modifying
• β -lactam antibiotics β -lactamase
Hetero-resistance and Viral Quasi Species :-
• It is said to be present when only a subset of the total microbial
population is resistant.
• Increased therapeutic failures and mortality is seen.
• Viral evolution due to drug and immune pressure Quasi species.
• Quasi species are resistant to antiretroviral agents failure of
Resistance due to Enhanced Excision of incorporated drug :-
• These drugs are incorporated into the viral DNA chain and cause
• E.g. Nucleoside reverse transcriptase inhibitors such as zidovudine are
2′-deoxyribonucleoside analogs 5′-triphosphate and compete with
• Mutation and antibiotic selection of the resistant mutant are the
molecular basis for development of resistance in many bacteria,
viruses, and fungi.
• Mutations are not caused by drug exposure. They occur as a survival
advantage, when drug is present.
• Mutations may occur in the gene encoding
(1) The target protein, altering its structure so that it no longer binds
(2) A protein involved in drug transport
(3) A protein important for drug activation or inactivation
(4) In a regulatory gene or promoter gene affecting expression of the
target, a transport protein, or an inactivating enzyme
• Suboptimal dosing strategies selective kill of the more susceptible
population, which leaves the resistant isolates to flourish.
• A single-step mutation high degree of resistance.
• The Multi-step mutation clinically significant resistance.
• E.g : Combination of pyrimethamine and sulfadoxine inhibits
Plasmodium falciparum’s folate biosynthetic pathway via inhibition of
dihydrofolate reductase (DHFR) by pyrimethamine and
dihydropteroate synthetase (DHPS) by sulfadoxine.
Hypermutable Phenotypes :-
• The ability to protect genetic information from disintegrating and also
to be flexible enough to allow genetic changes.
• This is accomplished principally by the
- Insertion of the correct base pair by DNA polymerase III
- Proofreading by the polymerase
- Postreplicative repair.
• Mutator (Mut) phenotypes antibiotic resistance .
Quorum sensing :-
• Microbes communicate with each other and exchange signaling
chemicals (Autoinducers) coordinate gene expression for virulence,
conjugation, apoptosis, mobility and resistance.
• QS signal molecules AHL, AIP, AI-2 & AI-3 have been identified in
• Gram-positive bacteria use processed oligo-peptides to
• Several QS inhibitors molecules have been synthesized AHL, AIP,
and AI-2 analogues Potent Virulence inhibitors.
• QS controls virulence factor production in Gram-positive human
pathogens including S. aureus, Listeria monocytogenes, Enterococcus
faecalis, and Clostridium perfringens
• V. cholera, P. aeruginosa Gram negative bacteria .
GENE TRANSFER :-
• Drug resistance may be acquired by passage of the trait vertically to
daughter cells, but more commonly it is acquired by horizontal
transfer of resistance by,
• Horizontal transfer of resistance genes is greatly facilitated by
Mobile genetic elements
Plasmids Transducing Transposable Integrons Gene
phages elements cassettes
Insertion sequences Transposons Transposable phages
• Insertion sequences do not encode resistance, but they function as
sites for integration of other resistance-encoding elements.
• Transposons are insertion sequences that also code for drug
resistance & other function.
• Transposon move between chromosome and plasmid thus
“hitchhike” the resistant gene out of the host and into a recipient.
Transduction - Is acquisition of bacterial DNA from a phage that has
incorporated DNA from a previous resistant host bacterium.
e.g. strains of S. aureus.
Transformation - Is the uptake and incorporation into the
host genome by free DNA released into the environment by
other bacterial cells. E.g. Penicillin resistance in
Pneumococci and Neisseria.
Conjugation - Is gene transfer by direct cell-to-cell contact through a
sex pilus or bridge.
• Multiple resistance genes can be transferred in a single event.
• Genetic transfer by conjugation is common among gram-negative
bacilli, and Enterococci.
CROSS RESISTANCE :-
• Acquisition of resistance to one AMA conferring resistance to
another AMA to which the organism has not been exposed
e.g. - resistance to one sulfonamide means resistance to all others,
-resistance to one tetracycline means insensitivity to all others
• Partial cross resistance is sometimes seen in unrelated drugs
e.g. - between tetracyclines and chloramphenicol
- between erythromycin and lincomycin.
• Cross resistance may be
Two-way, e.g. between erythromycin and clindamycin and vice versa
One-way, e.g. development of neomycin resistance by
enterobacteriaceae makes them insensitive to streptomycin but many
streptomycin-resistant organisms remain susceptible to neomycin.
Prevention of drug resistance :-
No indiscriminate and inadequate or unduly prolonged use of AMAs
should be made.
Prefer rapidly acting and selective (narrow spectrum) AMAs.
Use combination of AMAs for prolonged therapy e.g. tuberculosis,
Intensive treatment for notorious organisms.
• Essentials of Medical Pharmacology Sixth Edition - KD TRIPATHI MD
• Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS
• LaSarre B, Federle MJ. Exploiting Quorum Sensing To Confuse
Bacterial Pathogens. Microbiology and Molecular Biology Reviews :
MMBR. 2013;77(1):73-111. doi:10.1128/MMBR.00046-12.