Promis­ing New An­timi­cro­bials

Note­wor­thy

Amid the tur­moil and un­cer­tainty of our times, one fact is un­de­ni­able: mi­crobes con­tinue to evolve. Their very re­silience and adapt­abil­ity have led to the cur­rent cri­sis of an­timi­cro­bial re­sis­tance as mi­crobes de­velop re­sis­tance to the an­timi­cro­bial drugs used to con­trol them. Obliv­i­ous to ge­og­ra­phy or bor­ders, the spread of re­sis­tant mi­crobes has be­come a threat to hu­man health. Fu­ture sce­nar­ios even en­vi­sion rapidly es­ca­lat­ing death tolls from our in­abil­ity to ef­fi­ciently man­age mi­cro­bial pathogens.

Tack­ling the an­timi­cro­bial re­sis­tance cri­sis re­quires mul­ti­ple ap­proaches. These range from un­der­stand­ing con­sump­tion trends and lim­it­ing use in sec­tors such as an­i­mal rear­ing, where re­sis­tance has es­ca­lated, to iden­ti­fy­ing new an­tibac­te­r­ial com­pounds.

(a) Top, gene com­po­si­tion of the lrc BGC. Bot­tom, post­trans­la­tional mod­i­fi­ca­tion of the LrcA pre­cur­sor pep­tide leads to the pro­duc­tion of LAR and its variant(s). The pro­teins B1 and B2 rec­og­nize and cleave the leader pep­tide, re­spec­tively, fol­lowed by the cy­cliza­tion by LrcC. LrcF cleaves the ter­mi­nal glycine lead­ing to the for­ma­tion of LAR‑B and LAR‑C vari­ants. It re­mains un­known how the sec­ond isopep­tide bond of LAR‑B is formed. Source

A re­cent pa­per, the re­sult of a multi­group col­lab­o­ra­tion (from Mc­Mas­ter Uni­ver­sity in Canada, Gerry Wright's group and from U. of Illi­nois at Chicago, the groups of Alexan­der Mankin, Nora Vazquez-Laslop and Yury Po­likanov), re­ports on a novel broad-spec­trum pep­tide an­tibi­otic that tar­gets the bac­te­r­ial ri­bo­some. The au­thors gen­er­ated a col­lec­tion of strains from which they pre­pared and screened ex­tracts for an­tibac­te­r­ial ac­tiv­ity against Gram-neg­a­tive strains. By aim­ing for slow-grow­ing and po­ten­tially over­looked environ­mental strains and care­fully teas­ing out ac­tiv­i­ties in the ex­tracts, they dis­cov­ered the novel pep­tide an­tibi­otic lar­i­o­cidin (LAR). This pep­tide be­longs to a group of nat­ural prod­ucts known as RiPPs that are syn­the­sized via the ri­bo­some from pep­tide-en­cod­ing genes. The pre­cur­sor pep­tide gen­er­ated is then post-trans­la­tion­ally mod­i­fied, in this case re­sult­ing in a lasso pep­tide with a char­ac­ter­is­tic 3D shape that makes these mol­e­cules highly sta­ble.

Al­though many pep­tides with an­timi­cro­bial ac­tiv­ity are known, LAR has unique prop­er­ties. It is the only RiPP known to tar­get the 30S ri­bo­so­mal sub­unit. By do­ing so, it in­hibits trans­la­tion elon­ga­tion and in­duces mis­cod­ing. This pep­tide also had broad-spec­trum anti­microbial ac­tiv­ity against both Gram-pos­i­tive and Gram-neg­a­tive bac­te­ria.

It is en­cour­ag­ing to know that new an­timi­cro­bials can still be ob­tained by tweak­ing long-tried ap­proaches based on cul­tur­ing to screen en­vi­ron­men­tal mi­crobes. Hope­fully, such dis­cov­er­ies will lead to the de­vel­op­ment of much-needed an­tibac­te­r­ial drugs.

 

("Note­wor­thy" is the new for­mat for STC's Thurs­day posts. Please read our Jan 20, 2025 post out­lin­ing this and other changes in our blog.)