Tetra­cy­cline: As­sas­sin, Aphro­disiac, ...

by Merry Youle

...Agent Pro­vocateur, Chore­o­g­ra­pher

When first used clin­i­cally, tetra­cy­cline was ef­fec­tive against mem­bers of the genus Bac­teroides, Gram-ne­ga­­tive anaer­obes that make up 20–30% of our colonic bac­terial pop­u­la­tion. Though usu­ally well-be­haved, Bacter­oides are op­por­tunis­tic pathogens ca­pa­ble of caus­ing life-threat­en­ing in­fec­tions if the colon is per­fo­rated. Now, vir­tu­ally all Bac­teroides clin­i­cal iso­lates are re­sis­tant to tetra­cy­cline, and all re­sis­tant Bac­teroides con­tain a con­jugative trans­po­son (CTn) that car­ries the re­sis­tance gene.

Bac­teroides frag­ilis

CTns pro­mote mat­ing and their own trans­fer from host to host, some­times to a dif­fer­ent species or genus, some­times even cross­ing the gram negative/gram pos­i­tive di­vide.

CTn-DOT car­ries a gene for tetra­cy­cline re­sis­tance and is wide­spread among Bac­teroides species in the hu­man colon. It also car­ries an operon com­posed of three reg­u­la­tory genes. Brief ex­po­sure of a Bac­teroides con­tain­ing CTn-DOT to low lev­els of tetra­cy­cline stim­u­lates ex­pres­sion of this re­gulatory operon ~20-fold. This re­sponse ac­ti­vates the CTn-DOT ex­ci­sion and trans­mis­sion genes which leads to a 10,000-fold in­crease in tran­fers. Thus not only does tetra­cy­cline se­lect for resist­ant bac­te­ria, it stim­u­lates mat­ing and the trans­fer of re­sis­tance to new hosts. Pretty clever, for a mol­e­cule!

Tetra­cy­cline struc­ture

But that is not all that these reg­u­la­tory genes do. Ac­cording to a re­cent re­port, these genes also af­fect tran­scrip­tion of host chro­mo­so­mal genes. In other words, an in­com­ing mo­bile el­e­ment (e.g., CTn-DOT) can have "a rather sub­stan­tial ef­fect on ex­pres­sion of genes in a re­cip­i­ent" cell. CTn-DOT genes up­reg­u­late 36 host genes, some in­creas­ing 148-fold. Just as many genes were sig­nif­i­cantly down­reg­u­lated. The down­reg­u­lated genes in­cluded var­i­ous iden­ti­fi­able genes, but the re­searchers saw no co­her­ent pat­tern. Most of the up­reg­u­lated genes were of un­known func­tion and the ef­fects of their up­reg­u­la­tion were not de­tected. How­ever, one ef­fect was re­ported: the in­duct­ion of nu­mer­ous genes of a cryp­tic CTn which re­sulted in its mo­bi­liza­tion and trans­fer.

These ef­fects re­quired the reg­u­la­tory genes and ex­po­sure to te­tracycline. The au­thors pon­dered why tetra­cy­cline is the sig­nal for such a so­phis­ti­cated reg­u­la­tory sys­tem. They point out that te­tracycline has been used as a clin­i­cal an­tibi­otic for only a very short time, cer­tainly by evo­lu­tion­ary stan­dards. Granted, tetra­cy­cline has been pro­duced by actin­o­mycetes much longer, but Bacte­roi­des, be­ing ob­lig­ate anaer­obes, are not usu­ally ac­tive in the same en­vi­ron­ments as the aer­o­bic ac­tinomycetes. The re­searchers fa­vored a more in­trigu­ing hy­poth­e­sis:  tetra­cy­cline might be just a stand-in for the real in­ducer which is some plant phe­no­lic com­pound that re­sem­bles part of the tetra­cy­cline mol­e­cule. CTns in Bac­teroides trans­fer only when the cells mate on a solid sur­face. Thus it could be use­ful to know when your host has made con­tact with a plant par­ti­cle in the co­lon. The prob­lem with this hy­poth­e­sis, they ad­mit, is that they have not yet found such a com­pound.

Sound­ing a note of con­cern, the au­thors ob­served that dis­cus­sions of con­se­quences of an­tibi­otic treat­ment fo­cus on "pos­si­ble dis­rup­tions in the pop­u­la­tion struc­ture of bac­te­r­ial mi­croflora and in­creased se­lec­tion for re­sis­tant strains. Our find­ings sug­gest an­other rea­son for con­cern; expo­sure to an an­tibi­otic could trig­ger changes in gene ex­pres­sion in some in­testi­nal bac­te­ria with as yet un­known con­se­quences."