The View From Here – by Ju­lian Davies

Zabriskie Point. Source

We have in­vited a num­ber of dis­tin­guished mi­cro­bi­ol­o­gists to share some of their thoughts with us.

by Ju­lian Davies

The Par­vome

This is in re­sponse to Mark Martin's prompt*; he is an in­teresting and eclec­tic char­ac­ter. Well, I was not in­clined to write any­thing, but since this week has been spent on grant writ­ing (for not very much money, this be­ing the style in Canada) and to­day, be­ing a sunny day, I de­cided to cut the grass but the han­dle kept on com­ing de­tached from the push mower which put me in a good mood for a rant (not a blog); I am also up­set about the fact that Ro­ger Fed­erer lost again and I don't like to see bad things hap­pen to my he­roes. But to come back to Mark's prompt, why do mi­crobes make so many small mol­e­cules?

To start with I apol­o­gize for the fact that the ques­tion is bi­o­log­i­cally in­cor­rect, since the only peo­ple who can an­swer "why" ques­tions are priests. How­ever, you know what I mean. I am very en­thu­si­as­tic about the fact that the sci­en­tific world is be­com­ing in­ter­ested in bio­mes and their im­por­tance to eu­kary­otic life; it is about time! Jeff Gor­don, Je­remy Nichol­son, and oth­ers have con­firmed the no­tion that bac­te­ria are re­ally good for us hu­mans and we can be­gin to think se­riously about mi­crobes as be­ing truly im­por­tant liv­ing be­ings. As you know, I have long been in­terested in how mi­cro­bial small mol­e­cules fit into this pic­ture.

As I pointed out in an ear­lier let­ter, there is a hu­mungous mi­cro­bial world of small mol­e­cules of great struc­tural di­ver­sity (Mark Mar­tin sug­gested "par­vome," from the Latin, parvus, for "small," and I agree; I have al­ways wanted my own "-ome.") Mi­crobes are the most ac­com­plished chemists on earth; in­ter­est­ingly, one of the great­est chal­lenges for or­ganic chemists is to de­sign syn­thetic ap­proaches to these mol­e­cules and many nat­u­rally-oc­cur­ring com­pounds re­main to be so made. But these small mol­e­cules were not pro­duced to be PhD projects and nei­ther were they made to cure our in­fec­tious dis­eases. The lat­ter is one of the best ex­am­ples of an­thro­pocen­tric think­ing, in my opin­ion. We use bac­te­r­ial small mol­e­cules as drugs pre­cisely be­cause they ex­hibit dose re­sponse curves. At high doses they are good for us but at low doses they must pos­sess ac­tiv­i­ties that are good for mi­crobes, more es­pe­cially for mi­cro­bial com­mu­ni­ties (the only way that mi­crobes ex­ist in na­ture – well, maybe not in in­va­sive in­fec­tions).

So what do small mol­e­cules do? Our stud­ies show that all nat­ural prod­ucts are bioac­tive, in the sense that at low (sub-in­hibitory) con­cen­tra­tions they mod­u­late bac­te­r­ial tran­scrip­tion. De­pend­ing on the com­pound and its tar­get, each small mol­e­cule in­flu­ences a dis­tinct spec­trum of pro­moter re­sponses. To me and some oth­ers, this im­plies that in the en­vi­ron­ment, bac­te­r­ial com­mu­ni­ties are mod­u­lat­ing their ac­tiv­i­ties us­ing a wide range of small mol­e­cule sig­nals.

An­tibi­otic bind­ing to bac­te­r­ial ri­bo­somes: many tar­get sites for small mol­e­cule sig­naling. Source

I could say that this was a form of home­osta­sis, but it is pre­ma­ture to make this con­clu­sion. I could also say that bac­te­ria all have their own cell phones but this is a pri­mitive an­thro­po­mor­phism! I think we must ac­cept that this is a dif­fer­ent form of cell-cell sig­nal­ing than is nor­mally dis­cussed, since the small mol­e­cule lig­ands in­ter­act with macro­mol­e­c­u­lar re­cep­tors such as ri­bo­somes, or the DNA repli­ca­tion, tran­scrip­tion, and cell wall complex­es. All this re­mains to be proven, of course, and some good imag­ing stud­ies in soils and other en­vi­ron­ments would help.

On the other hand, some small mol­e­cules are so toxic that it is dif­fi­cult to see how they could be any­thing other than real an­tibi­otics. A good ex­am­ple is the enediyne class pro­duced by a num­ber of dif­fer­ent bac­te­ria and used as an­ti­tu­mor agents. Bac­te­ria make them, use them (for what pur­pose?), and sur­vive! The self-pro­tec­tion mech­a­nisms must be ex­tremely ef­fec­tive since one slip means death. In­ci­den­tally, I won­der if the nat­ural bac­te­r­ial pro­tec­tion mech­a­nisms could be used to con­trol the ac­tiv­i­ties of these po­tent com­pounds dur­ing can­cer chemother­apy? Some­one must have thought of this.

Fi­nally, there has been much dis­cus­sion of late about the "en­vi­ron­men­tal re­sis­tome." One can cer­tainly find en­doge­nous an­tibi­otic re­sis­tance genes in most bac­te­r­ial pop­u­la­tions by cloning and test­ing in the lab. But is this their real func­tion in na­ture? Could re­sis­tance be due to pleiotropic ef­fects? Is much of the clin­i­cally sig­nif­i­cant re­sis­tance sim­ply due to the over-ex­pres­sion of a he­terologous gene in a dif­fer­ent cy­to­plasm?

So there you are. I hope that you have no con­cerns about my san­ity; you can blame this post on Mark!

Yours in won­der (about mi­crobes).

*Mark's prompt: I would love to see a post from Ju­lian Davies from UBC over his idea (pre­sented at ASM) that there ex­ists a mi­cro­verse of small mol­e­cules in na­ture which have pro­found ef­fects on mi­crobes in the nat­ural world.

Ju­lian Davies is Pro­fes­sor emer­i­tus at the Uni­ver­sity of British Co­lumbia and a Fel­low of the Royal So­ci­ety. He pre­vi­ously contri­but­ed a let­ter to this blog.