When dealing with bacterial toxins, there are three varieties of microbes that develop in your petri dish: toxic, resistant, and susceptible. Initially, there are only toxic and vulnerable bacteria. Over time some bacteria become resistant and outbreed the toxic microbes because it is an energy load to produce toxins. Once the toxin producers disappear, the excess load to be resistant is a disadvantage and normal microbes prevail. For anti-malarials especially in Southeast Asia, this does not happen. Normal strains of malaria do not reemerge with the absence of these drugs. Are antimalarials working differently than toxins are other forces propping up resistant strains? All ideas are welcome
Hi,
Those papers may explain the problem via evolutionary basis ...
" (...) stably resistant lines of P. chabaudi (27) and P. vinckei (28) have been produced by low-level drug treatments, usually lasting over many blood passages, with gradual increases in drug concentration. In this way resistance of P. vinckei to chloroquine was raised from 5 mg/kg to 200 mg/kg of body weight (the maximum dose tolerated by mice) (28); the resistance of P. chabaudi, starting with cloned material, was raised from 2 mg/kg to 30 mg/kg of body weight (27). In both species the resistance finally obtained was stable after repeated passaging."
" (...) high-level resistance is due to the combined action of several mutant genes at different chromosomal loci. "
Article The genetics of drug resistance in malaria parasites
" Evidence of association between several alleles in P. falciparum multi-drug resistance (Pfmdr) gene and chloroquine-resistance was reported in 1990 [11]. However, the K76T mutation in P. falciparum chloroquine resistance transporter gene (Pfcrt_K76T) mostly associated with the Pfcrt_72C-73V-74I-75E-76T haplotype in Africa is known as the strongest chloroquine-resistance marker in P. falciparum."
" The co-inheritance of several mutations in P. falciparum Apicoplast Ribosomal Protein S10 (Pfarps10) gene [Pfarps10_127M-128Y/H], the P. falciparum ferredoxin (PfFd) gene [Pfd_ 193Y], the PfCRT gene: [Pfcrt_326S-356T], and the PfMDR2 [Pfmdr2_T484I] were shown to constitute a genetic background that allows for the emergence of mutations in the P. falciparum kelch 13 gene [27], a known artemisinin resistance locus [28–30]. Tis haplotype is referred to as artemisinin-resistant parasite genetic background (Artresistant PGB). "
https://malariajournal.biomedcentral.com/track/pdf/10.1186/s12936-019-2986-5.pdf
" Increased gene copy numbers and levels of expression of P. falciparum multiple-drug resistance gene 1 (pfmdr1) were associated with decreased susceptibility to MQ and halofantrine (114). Amplification of the P. falciparum GTPcyclohydrolase I (pfgch1) gene, associated with resistance to antifolate drugs, has also been described (44, 117, 125). Genomic breakpoints are frequently located in AT-rich regions or near homopolymeric tracks of poly(A) or poly(T) nucleotides (126, 127). Gene amplification is often unstable and can revert to single copy without pressure. However, DNA duplications flanked by distant A/T tracks could be a first step for desirable evolutionary events under selection pressure (127). "
https://cmr.asm.org/content/cmr/32/4/e00019-19.full.pdf
Best regards
Tomasz
Tomasz Grabowski For me what was surprising is that antifolates were in use against protozoa. I knew that poor analogs of folic acid were the first chemotherapeutic drug that had some success against juvenile leukemia by Dana Farber. I thought they were only used for cancer. Am I right that
these papers explain how drug resistance can be identified and is created via genetics? Is genetic-based drug resistance is different from acquiring immunity to microbial toxins? Toxin resistance always has a cost. and when the poison is absent this cost has no advantage and microbes with this ability become rare or no- existent. Do you think anti-folates would coselect for resistance to all anti-malarials?
Hi,
Cross-resistance is possible so ....
" The problem of antimalarial drug resistance is compounded by cross resistance, in which resistance to one drug confers resistance to other drugs that belong to the same chemical family or which have similar modes of action. "
https://www.who.int/malaria/areas/treatment/drug_efficacy/en/
" Clyde and Shute (1957) found incomplete cross-resistance between pyrimethamine and proguanil, and Peters (1975) found the same between the sulfonamides and sulfones. Multidrug resistance was described by Earle et al. (1948) in a Central American strain resistant to proguanil, mepacrine, and quinine."
"(...) as had been previously reported (Winstanley et al., 1995), there was significant in vitro cross-resistance between pyrimethamine and trimethoprim. Alleles that included the S108N mutation were more resistant to both trimethoprim and pyrimethamine."
https://pharmrev.aspetjournals.org/content/57/1/117
" There are concerns that widespread use of cotrimoxazole for prophylaxis may result in selection of P. falciparum parasites with cross-resistance to other antifolate drugs such as sulphadoxine-pyrimethamine (SP), which is used as intermittent preventive treatment of malaria in pregnancy (IPTp) and in infants (IPTi) in Africa."
Article The prevalence and antifolate drug resistance profiles of Pl...
Best regards
Tomasz
Thank you, Sorry Tomasz, I am an English Teacher so I must point out
co-select or co-selection is a synonym for cross-resistance that is perhaps slightly broader and more involved with evolution but still means the same thing. There is the problem with English too many synonyms
co-selection because it comes from a different biological domain than medicine is virtually unknown in that field
Article Co-selection of antibiotic and metal resistance
have you ever heard of it? The only reason I know it was through some ecological medicine articles. Still, both cross-resistance and co-selection seem promising how would you suggest testing them? Also, you have given me a lot of reading to do Thanks
Maybe now one of our RG colleagues will take part in the discussion :) the topic is wide ...
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