π Health and biotech
How science is preparing for antibiotic resistance

The multiple forms of antibiotic resistance

Agnès Vernet, Science journalist
On March 16th, 2022 |
3 min reading time
Philippe Glaser
Philippe Glaser
Research Director in Ecology at Institut Pasteur
Key takeaways
  • Antibiotic resistance occurs when a bacterium survives a dose of antibiotics that would normally kill it.
  • There is a reservoir of genes responsible for antibiotic resistance and a wide variety of biological mechanisms.
  • Antibiotic treatments will select for resistant bacteria and promote the transfer of this ability from one bacterium to another.
  • A better understanding of the mechanisms involved in resistance is essential for developing more effective antibiotics or combinations of treatments.

Antibi­ot­ic resis­tance is a com­plex prob­lem. It occurs when a bac­teri­um sur­vives a dose of antibi­otics that would nor­mal­ly kill it. This con­cept is thus direct­ly linked to the way in which the antibi­ot­ic mol­e­cule acts on the micro-organ­ism and there­fore to how the micro-organ­isms can pro­tect them­selves. There is a wide vari­ety of bac­te­ria that are poten­tial­ly path­o­gen­ic to humans and ani­mals, and many dif­fer­ent antibi­ot­ic mol­e­cules. Under­stand­ing their inter­ac­tions, both at the lev­el of a cell and at the lev­el of a pop­u­la­tion of cells, is essen­tial for under­stand­ing antibi­ot­ic resistance.

Molecular shields

There are two types of resis­tance: intrin­sic and acquired. The first applies, for exam­ple, to bac­te­ria whose very struc­ture forms a pro­tec­tive lay­er against a tox­ic mol­e­cule. Take, for exam­ple, van­comycin, an antibi­ot­ic that is effec­tive against Staphy­lo­coc­cus aureus or ente­ro­coc­ci, which are gram-pos­i­tive bac­te­ria. But for Escherichia coli or Pseudomonas aerug­i­nosa, which are gram-neg­a­tive, this antibi­ot­ic does not reach its tar­get. These bac­te­ria are so-called because they have a dou­ble mem­brane that pre­vents the pen­e­tra­tion of the stain devel­oped by the Dan­ish bac­te­ri­ol­o­gist Hans Chris­t­ian Gram and thus cer­tain antibi­otics. The tar­get of van­comycin is indeed locat­ed between these two mem­branes. Oth­er mol­e­cules capa­ble of cross­ing the out­er­most mem­brane, such as antibi­otics of the peni­cillin fam­i­ly, must there­fore be used against these types of bacteria.

It is acquired antibi­ot­ic resis­tance that explains the cri­sis we are cur­rent­ly expe­ri­enc­ing. It con­cerns micro-organ­isms that were pre­vi­ous­ly sen­si­tive to a mol­e­cule to treat an infec­tion and no longer are. Bac­te­ria have two ways of learn­ing to pro­tect them­selves from a tox­ic mol­e­cule. As they divide, they can accu­mu­late muta­tions which, by alter­ing the tar­get of the antibi­ot­ic or pre­vent­ing it from enter­ing the cell, ren­der it ineffective.

The sec­ond way of acquir­ing resis­tance relies on mobile genet­ic ele­ments, i.e. pieces of DNA that can move from one cell to anoth­er. These are usu­al­ly plas­mids, cir­cu­lar, aux­il­iary mini-chro­mo­somes that bac­te­ria exchange, even between dif­fer­ent species. These plas­mids are for­mi­da­ble from the point of view of antibi­ot­ic resis­tance because they can car­ry sev­er­al genes for resis­tance to dif­fer­ent class­es of antibi­otics. A bac­teri­um can thus become mul­ti-resis­tant by the sim­ple acqui­si­tion of such a plasmid.

Bacterial ecology

Plas­mids, and the resis­tance genes they car­ry, are also respon­si­ble for much of the antibi­ot­ic resis­tance of the com­men­sal bac­te­ria of our diges­tive sys­tem. These bac­te­ria can receive plas­mids con­tain­ing resis­tance genes from bac­te­ria in their envi­ron­ment that are less well adapt­ed to the gut ecosys­tem. Resis­tance will thus spread among the micro­bio­ta, con­sti­tut­ing a “silent reserve” with clin­i­cal con­se­quences that have yet to be evaluated.

The action of an antibi­ot­ic depends on the liv­ing con­di­tions of a bac­teri­um, which some­times com­pli­cates the inter­pre­ta­tion of lab­o­ra­to­ry diag­noses. A bac­teri­um may be sen­si­tive to an antibi­ot­ic in a petri dish, but resis­tant in the patient, or vice ver­sa. The action of the treat­ment and the response of the bac­te­ria vary accord­ing to the envi­ron­ment; they will not be iden­ti­cal in blood, urine or lab­o­ra­to­ry con­di­tions. Fur­ther­more, the antibi­ot­ic alone can rarely elim­i­nate an infec­tion-caus­ing bac­teri­um because it works with the patien­t’s immune response. Work, such as our Seq2Diag project, aims to inte­grate these para­me­ters to improve diagnosis.

The study of resis­tance also includes the pop­u­la­tion dynam­ics of bac­te­ria. Dur­ing an infec­tion, a large num­ber of bac­te­r­i­al cells in dif­fer­ent envi­ron­ments are involved and not all are iden­ti­cal. Those that are able to sur­vive the admin­is­tered dose of an antio­bi­ot­ic will take advan­tage of the space freed by the sus­cep­ti­ble ones to multiply.

This strug­gle for space is at the very ori­gin of some antibi­otics and resis­tance genes. Many antibi­otics, such as strep­to­mycin, used to treat tuber­cu­lo­sis, have them­selves been iso­lat­ed from bac­te­ria. Bac­te­ria pro­duce these mol­e­cules to pro­tect their own space and to take over space from the sen­si­tive bac­te­ria with which they cohab­it. Log­i­cal­ly, a bac­teri­um that syn­the­sis­es an antibi­ot­ic is, in one way or anoth­er, resis­tant to that mol­e­cule. Antibi­otics and resis­tance are nat­ur­al phe­nom­e­na in the dynam­ics of many bacteria.

Predicting resistance

One of the main ques­tions fac­ing sci­en­tists today con­cerns the appear­ance of resis­tance. Can it be pre­dict­ed? The prob­lem is com­plex and relies large­ly on mon­i­tor­ing cir­cu­lat­ing strains and analysing their genomes. 

This involves com­pil­ing the genome sequences of bac­te­ria con­sid­ered to have an atyp­i­cal resis­tance pro­file. When the resis­tance mech­a­nism is not recog­nised in the genome, biol­o­gists will try to elu­ci­date the process involved and recon­struct its evo­lu­tion­ary his­to­ry. This infor­ma­tion could the­o­ret­i­cal­ly help pre­dict the emer­gence of new resis­tance. How­ev­er, new mech­a­nisms are rare and are now being detect­ed more quick­ly. WHO’s GLASS net­work mon­i­tors antibi­ot­ic-resis­tant bac­te­ria in low-income coun­tries. As part of the Pri­or­i­ty Research Plan, the Com­mis­sari­at aux investisse­ments d’avenir is fund­ing the devel­op­ment of a data­base of bac­te­r­i­al genomes linked to antibi­ot­ic resis­tance. This tool, called ABRomics, will bring togeth­er, in a sin­gle struc­ture, all the fre­quent and rare resis­tances iden­ti­fied in France and will allow to mon­i­tor their progress in real time. Such nation­al data­bas­es are deployed in var­i­ous coun­tries. They help to pre­dict the spread of strains that are dif­fi­cult to treat.

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