Immunology - Antimicrobial Therapies (Extra)

Question 1

crop-destroying fungi

Answer 1

account for perennial yield losses of ~20% worldwide, with a further 10% loss postharvest

Question 2

global mortality rate for fungal diseases

Answer 2

now exceeds that for malaria or breast cancer and is comparable to those for tuberculosis and HIV

Question 3

nystatin and the polyenes

Answer 3

The first antifungal chemicals used in human health care discovered in the 1950s

Question 4

copper and sulfur fungicides

Answer 4

first used to control crop disease more than 150 years ago

Question 5

systemic antifungals and fungicides

Answer 5

Today used as frontline treatments for fungal diseases in humans and plants, fungal pathogen control can be ephemeral because of the rapid development of resistance to the chemicals (fungi have highly plastic genomes and reproduce rapidly which quickly generates variants selected for resistance)

Question 6

Plant pathogens - pace of breakdown of antifungal protection

Answer 6

enhanced by monoculture cropping practices (large swathes of genetically uniform crops provide ideal breeding and feeding grounds for the rapid emergence of fungicide-resistant variants

Question 7

Humans - antifungal resistance

Answer 7

long periods of prophylactic treatment in at-risk patients

Question 8

six main classes of fungicides

Answer 8

• morpholines (inhibit two target sites within the ergosterol biosynthetic pathway delta14-reductase and delta8-delta7-isomerase (this reduces the risk of target-site resistance but their intrinsic antifungal activity spectrum is narrower than those of other antifungals))
• azoles (used also in animal infections, target the ergosterol biosynthetic pathway + the benzimidazoles (MBCs) which interfere with the cytoskeleton by binding to β-tubulin thus preventing the assembly of microtubules + the strobilurins (QoIs) and succinate dehydrogenase inhibitors (SDHIs) which both inhibit the electron transfer chain of mitochondrial respiration with the SDHIs inhibiting complex II (succinate dehydrogenase) and the QoIs inhibiting complex III (the quinone outside binding pocket of cytochrome b) + the anilinopyrimidines which may target mitochondrial signaling pathways)
• echinocandins (inhibit cell wall biosynthesis)
• pyrimidine analogs (interfere with nucleic acid biosynthesis)
• polyenes (bind ergosterol)

Question 9

Antifungals for the treatment of fungal diseases in the clinic and the field

Answer 9

progressed from the use of inorganic chemicals to the use of organic surface protectant chemicals and then to the use of systemically acting fungicides, licensed treatments for humans are limited to four frontline classes of drugs (polyenes (such as amphotericin B) disrupt the structure of cell membranes by sequestering the fungal membrane sterol ergosterol, pyrimidine analog 5-fluorocytosine (5-FC) blocks pyrimidine metabolism and DNA synthesis, echinocandins inhibit (1-3)-β-D-glucan synthase and disrupt cell wall biosynthesis, azoles block ergosterol biosynthesis through inhibition of lanosterol 14-α-demethylase)

Question 10

Antifungals for the treatment of fungal diseases in the field

Answer 10

approximately nine times more antifungal compounds are available to control crop diseases than to treat systemic animal infections, most fungicides for crop disease target mitochondrial function/ the cytoskeleton/ergosterol biosynthesis, azoles remain the dominant chemicals in the treatment of fungal infections with five licensed clinical azole antifungals and 31 available for crop protection

Question 11

Parallel drivers of fungicide resistance in the clinic and the field

Answer 11

crops bred for maximum productivity under the protection of broad-scale pesticide applications, increases in populations that are particularly susceptible because of age/ medical interventions/ HIV infection, medical advances resulting in greater initial survival rates for patients with cancer or organ transplantation can leave these patients susceptible to secondary attacks from opportunistic fungi leading to increasing use of antifungal drugs in clinical practice, the global movement of people and global trade in produce have hastened the free flow of fungal pathogens from country to country, new species of multidrug-resistant pathogenic fungi are emerging, Candida auris first described in Japan in 2009 after isolation from a patient’s ear is responsible for rapidly increasing hospital-acquired invasive infections worldwide (now resistant to all clinical antifungals and presents a threat to intensive care units because it can survive normal decontamination protocols), the emergence of resistance in Candida glabrata has coincided with this species becoming the predominant bloodstream pathogen recovered from patients largely because of the increasing prophylactic use of echinocandins and azoles

Question 12

Parallel evolution of resistance mechanisms in the clinic and the field

Answer 12

The selective pressure exerted on fungi by single-site-inhibiting fungicides has resulted in similar adaptations arising over time in disparate fungal species, mutations resulting in conformational changes to the drug target site are the most common form of resistance in pathogenic fungi, promoter changes resulting in up-regulation of the fungicide target are also common across clinical and plant-pathogenic fungi, reducing intracellular drug accumulation by up-regulation of efflux pumps such as adenosine triphosphate–binding cassette transporters or major facilitators which may result from promoter insertions or transcription factor gain-of-function mutations

Question 13

Dual use of azoles in the clinic and the field

Answer 13

multiple use seems to have promoted azole resistance in an opportunistic pathogen of humans (saprotroph A. fumigatus, colonizes decaying vegetation in fields + forests + compost heaps but is also capable of invading immunocompromised humans, repeated independent evolution of resistance to successive fungicides within numerous fungal species, differs fundamentally from that of antibacterial resistance, which is frequently transferred between pathogens of animals and humans via the “mobilome” of plasmids and phage, some evidence indicates horizontal gene transfer among fungi but this fungal gene transfer occurs over longer time scales than gene transfer among bacteria and the dynamics of resistance arising by this route is thus far negligible

Question 14

Prospects for diversifying the toolbox for fungal control

Answer 14

• Development of new antifungals (the rate of emergence of fungicide resistance is greater than the pace of fungicide discovery and the long registration process for new compounds adds further delays (situation parallels that for antibiotics))
• Stewardship of existing compounds (Robust global strategies (combining different modes of action either in mixtures or in alternating treatments may slow the emergence of resistance, where target-site mutations confer high levels of resistance lower doses of antifungals should be favored, improvements in molecular diagnostics are also needed for the identification of fungal pathogens so that antifungals can be used appropriately and for the detection of specific resistance alleles)
• Integrated disease management
  (develop more nonchemical control measures to use where effective fungicides are no longer available or to use in combination with fungicides to reduce the selective pressure on each component, in crops the development of innate disease resistance through the selection of major pathogen-resistance alleles is widely used to breed disease-resistant cultivars however this approach is slow, ,arker-assisted breeding can speed up the recombination of multiple disease-resistance alleles, but it still takes approximately a decade, transgene cloning, or gene editing, is faster still (requiring ~2 years), but no crops with transgenic antifungal disease resistance have yet been released commercially, the high degree of specificity between host and pathogen for major resistance genes means that pathogens can also rapidly evolve to overcome this strategy, “evolution-smart” disease-resistant crops with pyramided pathogen-resistance genes or mosaic deployment of resistant varieties may provide greater durability of disease control, minor resistance genes such as those for the antifungal chitinases and glucanases, carry the advantage of broad-spectrum activity but introduce the possible disadvantage of yield penalties as well as providing incomplete protection, further sources of genetic disease resistance can be found in the gene pools of crops’ wild relatives which may be introduced into modern crop varieties through introgression or transgenesis)
• In humans, advances in combination antiretroviral therapy to halt HIV-AIDS progression + gene therapies under development for cystic fibrosis + tissue engineering for rejection-free transplantation can reduce vulnerability to fungal infections in the corresponding patient cohorts, the rapidly growing fields of synthetic biology and epigenomics are now converging to develop antifungal treatments on the basis of RNA interference (RNAi)