The Tip of the Ice­berg

by David Hop­wood

We can­not read the pop­u­lar press – let alone the scienti­fic lit­er­a­ture – these days with­out re­al­is­ing that the resis­tance of dan­ger­ous path­o­genic bac­te­ria to cur­rently used an­tibi­otics is in­creas­ing at an alarm­ing rate. Me­thi­cillin (or mul­ti­ple) re­sis­tant Staphy­lo­coc­cus au­reus (MRSA) is the most talked about, closely fol­lowed by van­comycin re­sis­tant En­te­ro­coc­cus (VRE) as well as mul­ti­ple and ex­tremely re­sis­tant My­cobac­terium tu­ber­cu­lo­sis (MDR and XDR), but many clin­i­cians see drug re­sis­tant Gram-neg­a­tive res­pi­ra­tory pathogens as an even big­ger threat, es­pe­cially to im­muno-com­pro­mised pa­tients. It is com­mon­ly be­lieved that Na­ture re­vealed all her valu­able an­tibi­otics af­ter the Golden Age of an­tibi­otic dis­cov­ery that tailed off af­ter the 1960s. Drug com­pa­nies then turned to ro­botic or com­bi­na­to­r­ial chem­istry in the 1990s to fill the gap, but the tens of thou­sands of novel mole­cules syn­the­sised by this ap­proach turned out not to be "drug­gable." A promis­ing route to im­proved an­tibi­otics is to do com­plex med­i­c­i­nal chem­istry by ge­net­ics – combi­na­­torial biosyn­the­sis – ex­ploit­ing the flow­er­ing of the ge­netic un­der­stand­ing of nat­ural prod­uct biosyn­thetic path­ways in the late 1990s, but this is un­likely to gen­er­ate novel chem­i­cal classes of an­tibi­otics.

The po­si­tion of ery­thromycin (red) within the large ri­bo­so­mal sub­unit (RNA, dark green; pro­teins, light green). The view is look­ing from the ac­tive site into the pro­tein exit tun­nel. Ery­thromycin binds to the en­trance of the tun­nel and blocks the pro­gres­sion of nascent pro­teins. Source

Al­ter­na­tively – an­other prod­uct of the cur­rent ex­plo­sion of ge­nomic data for an­tibi­otic pro­duc­ing mi­crobes, es­pe­cially for the actin­o­mycetes, is the re­al­i­sa­tion that they en­code the ca­pac­ity to pro­duce a vast ar­ray of in­ter­est­ing chem­i­cal en­ti­ties that are not seen un­der typ­i­cal lab­o­ra­tory screen­ing con­di­tions. Pre­sum­ably these path­ways have evolved to serve spe­cific roles in the life of the or­gan­isms in their nat­ural habi­tats, and they are ex­pressed only un­der spe­cial con­di­tions of the phys­i­cal, chem­i­cal or bi­o­log­i­cal en­vi­ron­ment of the soil. How can we wake up these "sleep­ing" genes and re­veal the mol­e­cules that the path­ways gen­er­ate?

A re­cent pa­per from Kozo Ochi's lab­o­ra­tory pro­vides one pos­si­ble ap­proach. Their ear­lier work had de­scribed ex­am­ples of an­tibi­otic re­sis­tant Strep­to­myces mu­tants with al­tered ri­bo­somes that over-pro­duced cer­tain known an­tibi­otics. The present pa­per takes this con­cept a step fur­ther. Us­ing Strep­to­myces coeli­color and its blueg­mented an­tibi­otic acti­norhodin as a con­ve­nient test sys­tem, they showed that the facile se­lec­tion of suc­ces­sive mu­ta­tions to dif­fer­ent an­tibi­otics – up to eight over a pe­riod of a few months – re­sulted in a huge in­crease in acti­norhodin pro­duc­tion. At least a part of this was at­trib­uted to mod­i­fi­ca­tion of the strin­gent re­sponse, caus­ing them to name the ap­proach "ri­bo­some en­gi­neer­ing." The work in­volved the in­creased pro­duc­tion of a known mol­e­cule, but the ap­proach has also been shown to yield mea­sur­able quan­ti­ties of mol­e­cules not nor­mally de­tected – in other words to wake up sleep­ing genes.

The sig­nif­i­cance of this work ex­tends be­yond the spe­cific mech­a­nism in­volved in this case. Along with other re­cent demon­stra­tions of silent an­tibi­otic gene ac­ti­va­tion (for ex­am­ple, the work of the Lei­den group headed by Gilles van Wezel on the global reg­u­la­tor DasR of S. coeli­color which sens­es the level of the key nu­tri­ent N‑acetylglucosamine [See ref­er­ence, be­low]), it pro­vides a real hope that some of the enor­mous, cryp­tic po­ten­tial of the actin­o­mycetes to make chem­i­cally di­verse mol­e­cules may be ex­ploited in the next few years.

Ref­er­ence

Rigali, S., F. Tit­ge­meyer, S. Barends, S. Mul­der, A. W. Thomae, D. A. Hop­wood, and G. P. van Wezel. 2008. Feast or famine: the global reg­u­la­tor DasR links nu­tri­ent stress to an­tibi­otic pro­duc­tion by Strep­to­myces. EMBO Re­ports: ac­cepted for pub­li­ca­tion April 14.

Sir David Hop­wood is John Innes Emer­i­tus Fel­low at the John Innes Cen­tre, Nor­wich, Eng­land, and a Fel­low of the Royal So­ci­ety.