Siderophores, The Emerging Class Of Drugs In Treating Antibiotic Resistance Infections

Resistance to antibiotics is a major problem, researchers are facing across the globe. Researchers in recent years have designed new antibiotics based on molecules secreted themselves by bacteria and fungi. These “Trojan Horse” antibiotics, when appropriately targeted, may circumvent some of the most prevalent antibiotic resistance bacteria. Iron is important for the growth and virulence of bacteria but the concentration of iron in mammalian hosts is very low to sustain bacteria. Bacteria produce small molecules called siderophores (an “iron carrier”) under these extreme iron deficient events. These molecules are low molecular weight, highly selective and iron binders. Siderophores bind to iron tightly to form iron complexes recognized by bacterial receptors that initiate uptake by the bacterial cells. This active iron pumping process is an excellent example of growth regulation by molecular recognition that enables bacteria to survive under extremely low iron concentration.

Several research groups have tried to attach iron binding agents to antibiotics, especially penicillin-like drugs, but most of these experiments have failed because their siderophore targeting did not closely resemble natural bacterial siderophores. Few years back Hsiri has tested a compound, HT-06 and HT-07 siderophore conjugates and the studies revealed that these synthetic sideromycins have potent in vitro and in vivo activity against targeted gram-negative bacteria, including strains of Acinetobacter baumannii, E. coli, Pseudomonas aeruginosa and other pathogens, whereas the base antibiotic components alone (cephalosporin and loracarbef) had no in vivo efficacy.

Recently in October 2018, Japan-based company Shionogi announced that, The Lancet Infectious Diseases journal has published clinical results from the pivotal randomized controlled trial conducting by the company evaluating cefiderocol for the treatment of urinary tract infection involving multidrug-resistant gram-negative infections. Cefiderocol was shown to penetrate efficiently through the outer membrane of the gram-negative bacteria via active iron transporters. Cefiderocol is a promising candidate in treating serious infections caused by gram-negative bacteria including carbapenem-resistant strains. They have broad gram-negative activity carbapenem-resistant strains that include non-fermenters P. aeruginosa, A. baumannii and Stenotrophomonas maltophilia. Till now no siderophore drug has been approved by FDA. Cefiderocol is the first siderophore cephalosporin or siderophore drug that made its way forward into phase III trials. The encouraging results of the trial may result in the approval of first siderophore drug in the market. These drugs may revolutionize the treatment of antibiotic-resistant infections.

– Arpitha Shetty,
Research Analyst,
Infoholic Research