Introduction:
Multidrug resistance and increasing healthcare-associated infections arise from the same MDR strains of various gram-positive and gram-negative bacteria. But Staphylococcus aureus tops the list in these healthcare-associated infections, namely Methicillin resistant Staph. aureus or as its more commonly known MRSA. Increasing the complexity and stakes in the problem is a bacterial adaptation called persistence, which basically means on administration of a certain dose of antibiotics a subpopulation of bacteria switch onto this dormant activity stage which are highly tolerant towards antibiotics and can restart normal growth as antibiotic concentrations wane over time and comes to the infection back again. Given that many of the usual antibiotic mechanisms now have a bacterial resistance already evolved, research has opened up a new avenue into drugs targeting essential bacterial kinases which directly and fatally affect bacterial life processes. An anticancer agent, sorafenib has shown promise in its antibacterial activity and some of its analogues being developed also do present with a greater promise with more efficient antibacterial properties.
Research:
Sorafenib (SFN), an active anticancer drug was seen to be having antibacterial properties but it was uncertain what was the target of this drug, which was later discovered to be a kinase. SFN’s core is a known antibacterial scaffold being e N,N′-diarylurea motif. The research searches through different small molecule kinase inhibitors against S. aureus and confirms of SFN have antibacterial activity against it.
An extensive search into about 72 analogues of SFN organically synthesized in lab revealed an analogue called PK150 which proves to be having a tenfold anti-MRSA activity.
Further chemical proteomic studies did not reveal a potential kinase target but did reveal a lowering of menaquinone levels in the bacteria and also an increased activity of SspB proteins. A menaquinone deficiency influences membrane potential and PK150 and SFN were found to be decreasing it.
The activities of PK150 and SFN were compared with 2 agents, DMSO and rifampicin both of which showed a re-emergence of the bacterial infection after the concentrations waned but PK150 and SFN passed the tests by successfully decreasing the bacterial populations.
Conclusion:
SFN and one of its analogues PK150 are seen to be having good antibacterial activity with the added advantage of not inducing in-vitro resistance in the bacterial cells, they are seen to be dysregulating protein synthesis and secretion as they disturb menaquinone metabolism and also disrupting SspB levels in the bacterial cell eventually leading to cell lysis. It proved to be better than other antibacterial agents in combating MRSA resistance. More drugs that target kinase activity can be explored for antibiotic use and combating MDR problem looming over the Pharmaceutical and Healthcare industry today.
Reference : Le, P., Kunold, E., Macsics, R. et al. Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms. Nat. Chem. 12, 145–158 (2020).
By Vinit Chaudhari
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