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Artificial Intelligence in Health Combating XDR-bacteria as we approach 2050

1. Introduction bacteria to combat other surrounding bacteria and
microbes. This diverse class includes gramicidins,
8,9
The penicillin antibiotic was discovered in 1928, leading salivaricins, mutacins, nisins, bacteriocins, and other
to the development of numerous derivatives, such as lantibiotics, which hold promise for commercial use in
ampicillin, amoxicillin, cefotaxime, imipenem, and combating MDR bacteria. Recombinant technology is
meropenem, to combat bacterial infections. Unfortunately, now employed to express lantibiotic cyclase, lantibiotic
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drug-resistance proteins in bacterial extracts were detected synthetase, and lantibiotic transferase-peptidase to develop
as early as 1940. It took 25 years to isolate the amp gene in special types of cyclic peptide reactions, resulting in the
pBR322 and to demonstrate that purified Amp penicillinase
could cleave penicillin in vitro. Since then, drug companies development of novel trypsin-resistant peptide antibiotics
have faced concerns that their new antibiotics might become against MDR bacteria. To avert MDR, it is imperative to
obsolete within a few months of their commercial release. avoid non-prescription and uncontrolled antibiotics and
refrain from releasing antibiotics or lantibiotics into rivers,
Modern multidrug-resistance (MDR) conjugative plasmids 10
in bacteria are associated with mobile elements, integrons, ponds, and seas.
integrases, transposases, and DNA topoisomerases, In ancient times, India and China were renowned
facilitating the emergence of new mdr genes that render for their rich tradition of herbal preparations to cure
newly developed antibiotics ineffective and economically diverse diseases, including bacterial and fungal infections.
unviable. Despite these challenges, scientists continued to However, during British rule, India’s ancient tradition of
develop new derivatives of penicillin (cephalosporins and herbal drugs waned, while China continued to prioritize
carbapenems), aminoglycosides (amikacin), quinolones herbal drugs. Nevertheless, studies from the United States
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(moxifloxacin, lomofloxacin), and many others. On the have demonstrated the efficacy of a phytodrug, artimisinin
other hand, bacteria have evolved to carry genotypes such derivatives, to combat chloroquine-resistant malaria
as blaTEM, blaCTX-M, blaOXA-58, blaKPC, and blaNDM, parasites, as well as the ability of phytodrugs, taxol, and
which encode enzymes capable of inactivating all first- to topotecan to cure various types of cancer. Despite India’s
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fifth-generation PENEM antibiotics. Similarly, at least daily publication of numerous papers on phytoextracts
2
20 TET drug efflux derivatives have been sequenced, and with antibacterial activities, commercialization has
these enzymes efflux tetracycline or its higher derivatives been hindered by the low bioactive chemical content
such as doxycycline, minocycline, and tigecycline. and poor inhibitory power of such extracts. We made
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Chloramphenicol acetyltransferases (cat gene) were first our first important progress in isolating CU1 poly-
discovered in the inactivation of chloramphenicol by bromophenol-turpentine from Cassia fistula bark
acetylation, followed by the identification of AAC3’ and targeting RNA polymerase. 14,15 Furthermore, we developed
AAC6’ enzymes in bacterial plasmids responsible for a large-quantity purification process of NU2 poly-
acetylating streptomycin, amikacin, or erythromycin. The fluorophosphate-glycosides from Suregada multiflora root
discovery of StrA and StrB, two linked genes in plasmids, using thin-layer chromatography (TLC) and ultraviolet
has enhanced our understanding of how these two enzymes (UV)-shadowing, targeting MDR bacterial DNA
phosphorylate streptomycin to inactivate the tuberculosis topoisomerase I (in preparation). NU2 has also exhibited
(TB) drug. Lately, dozens of such isomers (APH2’, APH3’, an inhibitory role against the malaria parasite Plasmodium
and APH6’) have been discovered to inactivate most falciparum that resides in the human red blood cell.
amino-glycoside antibiotics. 3-5
Plant secondary metabolites are naturally produced
We also observe conventional point mutations in compounds that can inhibit soil bacteria. MDR bacteria
target enzymes, such as rpoB (RNA polymerase subunit) are known to proliferate in various environments,
and gyrA/B (DNA topoisomerase II subunits), which including soil, water (pond, river, sea, rain), chicken meat,
lead to the inhibition of the binding of drugs rifampicin milk, and human skin and hair. This constant exposure
and ciprofloxacin, respectively, to the target enzyme, to newer strains of MDR bacteria suggests that plants
thereby preventing them from exerting their inhibitory may continuously produce new antibiotics, making plant
effects. Consequently, the rate of approval for new extracts an ideal source for developing newer drugs against
antibiotic derivatives has decreased significantly, with only MDR bacteria and fungus. Our goal is to review the
2 – 5 approvals per year compared to hundreds released recent development and outcome of synthetic antibiotics,
annually between 1970 and 2000 for commercial therapy lantibiotics, and phytoantibiotics that are related to our
of infectious diseases. 6,7 phytodrug development program. However, we have
Lantibiotics are cyclic peptide antibiotics produced carefully avoided the development of new synthetic
by Streptomyces, Streptococcus, Lactobacillus, and other antibiotics, as many important reviews are available.
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Volume 1 Issue 2 (2024) 77 doi: 10.36922/aih.2284