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16.3.3 Molecular targets to fight against antiviral drug resistance
Antiviral drugs are medications specifically designed to treat viral infections by tar-
geting various stages of the viral life cycle or interfering with viral replication. These
drugs are used to prevent or treat a wide range of viral illnesses including influenza,
HIV/AIDS, hepatitis, herpes, and COVID-19. The choice of antiviral drug depends on
the specific virus, its characteristics, and the stage of the infection. Antiviral drug re-
sistance occurs when viruses, such as HIV, hepatitis, influenza, or herpes viruses, de-
velop genetic mutations or alterations that make them less susceptible or completely
resistant to the effects of antiviral drugs [53]. It’s important to note that antiviral
drugs are often used in combination (combination therapy) to reduce the likelihood
of drug resistance and increase treatment effectiveness. Here are some key examples
of molecular antiviral targets and how resistance can develop:
– HIV reverse transcriptase: HIV drugs like nucleoside and non-nucleoside reverse
transcriptase inhibitors (NRTIs and NNRTIs) target the reverse transcriptase en-
zyme. Resistance can occur when the virus mutates, leading to changes in the active
site of reverse transcriptase, making it less susceptible to the drug’s inhibition [54].
– Hepatitis C virus (HCV) NS5A protein: In HCV treatment, direct-acting antivirals
(DAAs) often target the NS5A protein. Resistance can emerge when mutations in
NS5A alter the binding site for the drug, reducing its effectiveness [55].
– Influenza neuraminidase: Resistance to neuraminidase inhibitors like oseltamivir
in influenza viruses can occur due to mutations in the neuraminidase gene. This
can reduce the drug’s ability to inhibit viral release from infected cells [56].
– SARS-CoV-2 spike protein: SARS-CoV-2 vaccines and monoclonal antibodies target
the spike protein on the virus’s surface. Variants of the virus, like Delta and Omi-
cron, have shown mutations in the spike protein, potentially affecting the virus’s
ability to bind to host cells and evade immune responses [57].
– Herpes simplex virus DNA polymerase: Drugs like acyclovir target the DNA poly-
merase of herpes si mplex virus. Mutations in HCV NS5A and NS5B proteins can
result in resistance to DAA drugs. Resistance can develop when mutations in the
viral DNA polymerase reduce the drug’s effectiveness [58].
– HIV protease and reverse transcriptase: Protease inhibitors in HIV therapy target
the viral protease enzyme. Mutations in the protease gene can lead to resistance
by altering the enzyme’s structure and function, reducing drug binding. Muta-
tions in the reverse transcriptase enzyme of HIV can lead to resistance against
nucleoside and non-nucleoside reverse transcriptase inhibitors [59].
– RdRp in RNA viruses: RNA-dependent RNA polymerase (RdRp) inhibitors like re-
mdesivir target the RdRp enzyme in RNA viruses. Resistance can arise through
mutations in the RdRp gene, affecting the drug’s ability to inhibit viral RNA repli-
cation [60].
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Hence, antiviral drug resistance is a significant concern in the field of virology and
infectious disease management. Research into new antiviral drugs and treatment
strategies continues to be a priority to combat resistance and improve outcomes for
individuals with viral infections. This helps maintain the effectiveness of antiviral
treatments in the face of evolving viruses.
16.3.4 Molecular targets to fight against antiparasitic
drug resistance
Antiparasitic drugs are medications used to treat infections caused by parasitic organ-
isms which include protozoa (single-celled organisms) and helminths (worm-like organ-
isms). These drugs are designed to kill or inhibit the growth of parasites within the
host’s body. Antiparasitic drugs are used to treat a wide range of parasitic infections
including malaria, trypanosomiasis, helminthiasis, and more. It’s important to note that
the choice of antiparasitic drug depends on the specific parasite, the location of the in-
fection, the patient’s medical history, and any potential drug interactions or side effects
[61]. Additionally, some antiparasitic drugs may require a prescription, while others
may be available over-the-counter or through public health programs. Proper diagnosis
and treatment by healthcare professionals are essential to effectively manage parasitic
infections. Drug resistance against parasites is a significant challenge in the field of par-
asitology and public health. Parasites, including protozoa (single-celled organisms) and
helminths (worm-like organisms), can develop resistance to antiparasitic drugs, which
are used to treat a wide range of parasitic infections in humans and animals. Drug re-
sistance against parasites is a complex and evolving problem that requires continuing
research, surveillance, and collaboration among healthcare providers, researchers, and
public health agencies to develop effective strategies for prevention and control. Molec-
ular targets against antiparasitic drug resistance vary depending on the specific para-
site and the class of drugs being used [61, 62]. Here are some key molecular targets and
mechanisms to combat antiparasitic drug resistance:
1. Plasmodium (malaria parasite):
– DHFR and dihydropteroate synthase (DHPS) enzymes are targeted by antima-
larial drugs like sulfadoxine-pyrimethamine. Resistance can result from mu-
tations in the DHFR and DHPS genes.
– Cytochrome b: Resistance can develop through mutations in the cytochrome b
gene. Atovaquone is one the effective inhibitory agent against the CytB gene.
– Pfcrt (Plasmodium falciparum chloroquine resistance transporter): A gene as-
sociated with resistance to the antimalarial drug chloroquine. Mutations in
this transporter protein are associated with resistance to chloroquine in ma-
laria parasites.
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– K13 Propeller Mutations: Mutations in the K13 gene linked to artemisinin re-
sistance in malaria parasites [63].
2. Trypanosoma (African trypanosomes and Chagas disease parasite):
– Trypanothione reductase is a potential target upon which trypanocidal drugs
like suramin and melarsoprol are subjected. Resistance can arise from muta-
tions in the trypanothione reductase gene [64].
3. Leishmania (Leishmaniasis parasite):
– Topoisomerase I and II receptors are targeted by antileishmanial drugs like
pentamidine and etoposide. Resistance may involve alterations in topoisom-
erase genes [65].
4. Helminths (parasiticworms):
– β-Tubulin: Targeted by dr ugs like albendazole and mebendazole. Resistance
can result from mutations in β-tubulin genes.
– Acetylcholine receptors: Targeted by antinematodal drugs like ivermectin.
Resistance may involve changes in acetylcholine receptor genes [66].
5. Schistosoma (Schistosomiasis parasite):
– Acetylcholinesterase is an effective target i.e., inhibited by praziquantel.
Changes in acetylcholinesterase function can lead to resistance [67].
6. Platyhelminthes (flatworms):
– Tetrahydrofolate dehydrogenase (THFD) is generally targeted by anti-flat-
worm drugs like praziquantel. Resistance may involve mutations in the THFD
gene [68].
7. Giardia lamblia (giardiasis parasite):
Glutamate dehydrogenase (GDH): Antigiardial drugs acts on GDH enzyme to elicit
potent pharmacological response. Resistance can result from mutations in the
GDH gene [69].
8. Trichomonasvaginalis (trichomoniasis parasite): pyruvate: ferredoxin oxidoreduc-
tase (PFOR) enzyme is targeted by metronidazole. Resistance may involve changes
in PFOR function [70].
9. Toxoplasma gondii (toxoplasmosis parasite): DHFR enz yme is generally targeted
by drugs like pyrim ethamine. Resistance can arise from mutations in the DHFR
gene [71].
Hereby, knowledge about mechanisms of antiparasitic drug resistance is essential for
developing effective treatments and strategies to combat parasitic infections. Re-
searchers continue to investigate new targets and approaches to overcome drug resis-
tance in various parasitic diseases.
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16.3.5 Molecular targets to fight against antifungal
drug resistance
Antifungal drugs are medications specifically designed to treat infections caused by any
fungal species, which can affect various parts of the body including the skin, nails, re-
spiratory system, and internal organs. Fungal infections can be caused by a wide range
of fungi including yeasts and molds. Antifungal drugs work by targeting different as-
pects of fungal biology to inhibit their growth or eliminate them. The choice of antifun-
gal drug depends on the type and severity of the fungal infection, the patient’s overall
health, and any potential drug interactions or side effects [72]. It is essential to consult
with a healthcare provider for a proper diagnosis and to determine the most appropri-
ate antifungal treatment. Further, antifungal resistance is a growing concern in health-
care, as it can bound the potential of antifungal drugs and complicate the treatment of
fungal infections. Fungal resistance mechanisms are similar to those of bacteria and in-
volve changes that allow the fungus to survive and continue growing despite the pres-
ence of antifungal medications. Antifung al drug resistance can occur due to various
molecular mechanisms in fungi. To combat this resistance, researchers target specific
molecular components or pathways [72, 73]. Here are some key molecular targets
against antifungal drug resistance:
– Ergosterol biosynthesis: Erg11 (cytochrome P450 14-alpha demethylase) is a fungal
enzyme targeted by azole antifungal drugs, leading to resistance when mutated.
– Beta-glucan synthase: Fks1 and Fks2 (β-glucan synthase) enzymes targeted by
echinocandin antifungals, with mutations causing resistance.
– Squalene epoxidase: This enzyme is generally targeted by allylamine antifungal
drugs like terbinafine. Resistance can result from mutations in the squalene epox-
idase gene [74].
– ABC and MFS transporters: Overexpression or mutations in ATP-binding cassette
(ABC) transporters as well as Major Facilitator Superfamily transporters can con-
fer resistance against various antifungal drugs, especially against azole class of
antifungal drugs.
– Chitin synthase: Resistance can develop through mutations in chitin synthase
genes, especially targeted by nikkomycin antifungal drugs.
– Beta-tubulin: Mutations in beta-tubulin genes can result in resistance against
benzimidazole antifungal drugs.
– Histone deacetylases (HDACs): Inhibiting HDACs can reverse resistance by alter-
ing gene expression in fungi.
– RNA polymerase: Some antifungal drugs target RNA polymerase in fungi and
hence disrupting transcription followed by protein synthesis [75, 76].
Understanding these molecular targets and the mechanisms of antifungal drug resis-
tance is crucial for developing novel antifungal therapies and strategies to combat
16 Identifying prominent molecular targets in the fight against drug resistance 417
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fungal infections effectively. The researchers continue to explore new ways to over-
come antifungal drug resistance as it remains a significant challenge in healthcare.
16.3.6 Molecular targets to fight against antibiotic
resistant tuberculosis
Tuberculosis (TB) is a mycobacterial infection caused by Mycobacterium tuberculosis,a
slow-growing bacterium that primarily affects the lungs but can also affect other parts
of the body. TB is a global health concern due to its widespread prevalence and poten-
tial for serious illness and mortality if not properly treated. TB remains a significant
public health challenge, and ongoing research and investment in prevention, diagnosis,
and treatment are essential to control and eventually eliminate this infectious disease.
Antibiotic-resistant TB is a form of TB, where Mycobacterium tuberculosis has devel-
oped resistance to one or more antibiotics commonly used to treat TB [77]. In drug-
susceptible TB (DS-TB), mycobacteria are susceptible to the most commonly used anti-
biotics such as isoniazid and rifampin, whereas multidrug-resistant TB (MDR-TB) ren-
ders to resist mycobacteria against at least isoniazid and rifampin, the two most potent
first-line TB drugs. Further, extensively, drug-resistant TB corresponds to mycobacteria
that are resistant not only to isoniazid and rifampin but also to fluoroquinolones and at
least one of three injectable second-line drugs (amikacin, kanamycin, or capreomycin).
Moreover, totally drug-resistant TB (TDR-TB) is a rare and controversial category,
where TB bacteria appear to be resistant to all known TB drugs [78, 79]. Antibiotic-
resistant TB is a form of TB that does not respond to standard antibiotic treatments due
to several mechanisms as mentioned in Figure 16.6 such as isoniazid and rifampicin,
which are typically used to treat TB.
By keeping in view such challenge, managing antibiotic-resistant TB is challeng-
ing and often requires prolonged treatment with more expensive and less effective
medications. It’s essential to follow proper public health measures to prevent its
spread and to develop new drugs and strategies to combat this global health issue. In
the context of antibiotic-resistant TB, there are several molecular targets that re-
searchers focus on to develop new drugs and therapies. These targets are specific
components or processes within the TB-causing bacteria (Mycobacterium tuberculosis)
that can be exploited to inhibit bacterial growth and overcome drug resistance [77–
79]. Some important molecular targets in resistant TB include
– RNA polymerase: Targeting the RNA polymerase enzyme can disrupt bacterial
transcription, inhibiting the synthesis of RNA and proteins necessary for bacterial
survival. Mutations in the rifampin-resistant rpoB (RNA polymerase beta subunit)
gene of Mycobacterium tuberculosis lead to resistance to rifampin [80].
– Cell wall synthesis: Mycolic acid synthesis enzymes are targeted to combat drug-
resistant Mycobacterium tuberculosis strains. Inhibiting enzymes involved in the
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synthesis of the mycobacterial cell wall, such as the enzyme InhA, can weaken
the bacterial structure and render it more susceptible to drugs [81].
– Isoniazid-resistant katG mutations: Mutations in the katG gene are associated
with isoniazid resistance.
– Efflux pumps: Efflux pumps are proteins that pump drugs out of the bacterial
cell. Inhibiting these pumps can prevent the bacteria from expelling antibiotics
and help overcome drug resistance. ABC transporters are targeted to inhibit drug
efflux in MDR organisms.
– DNA gyrase and topoisomerase: These enzymes are essential for DNA replication
and repair. Drugs that tar get them can interfere with bacterial DNA replication
and lead to cell death.
– Protein synthesis: Inhibitors of ribosomal proteins or the translation machinery
can disrupt bacterial protein synthesis, which is crucial for bacterial survival
[82, 83].
Researchers are constantly exploring these and other molecular targets to develop
new drugs and therapies to combat antibiotic-resistant TB effectively. Targeting multi-
ple pathways simultaneously is often necessary to tackle drug-resistant strains due to
the complex nature of TB and its ability to adapt to treatment.
Figure 16.6: Various mechanisms associated with antitubercular drug resistance.
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16.3.7 Molecular targets to fight against resistance in CNS agents
Central nervous system (CNS)-acting agents are drugs and substances that affect the
CNS, which includes the brain and spinal cord. These agents can have various effects
on the CNS including altering brain function, perception, mood, and consciousness.
These drugs that are used to treat neurological and psychiatric disorders can face re-
sistance due to various mechanisms [84]. Here are some molecular targets and strate-
gies to address resistance in CNS-acting agents:
1. Neurotransmitter receptors:
– Dopamine receptors: Targeted in the treatment of schizophrenia and Parkin-
son’s disease. Resistance mechanisms can involve altered receptor expression
or function.
– Serotonin receptors: Targeted in the treatment of depression and anxiety dis-
orders. Resistance may result from receptor desensitization or downregula-
tion [85].
2. GABAergic system:
– GABA receptors: GABAergic drugs are used to treat anxiety and epilepsy. Re-
sistance mechanisms may involve changes in receptor subunit composition
or expression [86].
3. NMDA receptors:
– Targeted in the treatment of neurodegenerative disorders and chronic pain.
Resistance mechanisms can include receptor desensitization or altered sub-
unit composition [87].
4. Neurotransmitter transporters:
– Dopamine transporter: Targeted by drugs used to treat attention deficit hy-
peractivity disorder. Resistance mechanisms may involve reduced drug bind-
ing or increased transporter activity [88].
5. Monoamine oxidase (MAO):
– Targeted by MAO inhibitors used to treat depression. Resistance can involve
increased MAO activity or alternative metabolic pathways [89].
6. Neurotrophins and their receptors:
– Trk receptors: Targeted in neurodegenerative diseases and mood disorders.
Resistance mechanisms may involve altered receptor expression or signal-
ing [90].
7. Ion channels:
– Voltage-gated sodium channels: Targeted by antiepileptic drugs. Resistance
can involve mutations in sodium channel genes.
– Calcium channels: Targeted in pain management and epilepsy treatment. Re-
sistance mechanisms can include altered channel expression or function [91].
8. BBB (blood–brain barrier) transporters:
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– Efflux transporters like P-glycoprotein at the BBB can limit the brain penetra-
tion of drugs. Strategies to overcome resistance involve developing drugs that
are less susceptible to efflux or modulating transporter function [92].
9. Epigenetic targets:
– DNA methyltransferases and HDACs can be targeted to modulate gene ex-
pression in psychiatric and neurodegenerative disorders. Resistance can in-
volve compensatory epigenetic changes [93].
Addressing resistance in CNS-acting agents often involves a combination of strategies,
including the development of new drugs that target specific molecular mechanisms,
optimizing drug delivery to the brain, and understanding the underlying genetic and
epigenetic factors contributing to resistance. Personalized medicine approaches based
on individual patient profiles are also being explored to enhance treatment efficacy.
16.4 Conclusions
Drug resistance poses a significant challenge to modern medicine, impacting the efficacy
of various therapies and leading to increased morbidity and mortality rates. To address
this critical issue, researchers have focused on understanding the molecular mecha-
nisms underlying drug resistance and identifying potential targets for intervention. This
compilation aims to provide a comprehensive overview of the molecular targets that
have emerged in the battle against drug resistance, covering diverse therapeutic areas
and highlighting the efforts of scientists till the date. The identification and characteriza-
tion of these molecular targets hold promise for the development of innovative strategies
to overcome drug resistance and improve patient outcomes. Additionally, the develop-
ment of combination therapies, where multiple drugs target different resistance mecha-
nisms simultaneously, can be a promising approach to combat drug resistance.
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