WillemVanSchaik

Great question and something I have actually done some work on :)

As you probably know 80% of the world's antibiotics are used in agriculture. Sometimes that use is perfectly valid (e.g. to treat mastitis in cows) but sometimes it is really problematic (e.g. as 'growth promoter' -> antibiotics increase growth/yields of farm animals with a mechanism that we poorly understand: this practice has been banned in the EU since the early 21st century, but it is still in use elsewhere).

As any use of antibiotics is likely to lead to resistance at some point, what we do in agriculture is create a massive reservoir of antibiotic-resistant bacteria and antibiotic resistance genes. The bacteria themselves may not be too much of a problem as bacteria are generally very well-adapted to the host. For example E. coli from chicken will have adapted to growing at 41 C, which is the body temperature of chicken, but is likely outcompeted by those bacteria that colonise humans (growing at 37 C).

However, the really tricky bit is that some genes that confer resistance to antibiotics are located on mobile genetic elements: pieces of DNA that can be exchanged readily between different bacteria. So, that E. coli from a chicken may not cause an infection in a human, but it may transfer its resistance genes to the E. coli that is present in the human gut. This might be the reason why some very high-profile resistance genes (Extended-Spectrum Beta-Lactamases [ESBLs] and Mobile Colistin Resistance [MCR] genes) have spread quickly: they were strongly selected for in agriculture through antibiotic use and then transferred to bacteria that were adapted to live in humans.

To quantify all these risks, however, is really difficult. I think there is now a consensus that most antibiotic resistance that we see in hospitals is caused by human use of antibiotics, as that directly selects for resistance in bacteria that have adapted to live in or infect humans. However, some of those resistance traits can be coming from animal reservoirs.

Hope this is (a bit) clear. Happy to expand further!

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I love biofilms! They have been around pretty much for billions of years: it is just a great way for bacteria to (literally) stick together and they are much less likely to be killed by microbial predators (amoebae) or immune cells. Antibiotics also don't penetrate biofilms well so... Disrupting biofilm formation is really difficult because they are so sticky (think of plaque on your teeth: you can only remove it by brushing; very difficult to do when somebody has a urinary tract infection!) . However, interesting progress is being made (also by colleagues in the institute) to develop materials that are intrinsically antibacterial and/or prevent biofilm formation. These could be used for implants, catheters etc.

The COVID19 pandemic is certainly showing how successful large, international teams of scientists can be in testing therapies against the virus. However, finding completely new drugs or developing vaccines takes a lot of time. Indeed, the drugs that now work against COVID19 (primarily dexamethasone) have been repurposed, rather than developed from scratch over the last few months.

Your idea to develop drugs that can be transported into bacteria is excellent. Indeed, people are studying this, right now! For example, iron uptake system can be used for bacteria to take up antibiotic-siderophore complexes (siderophores are products made by bacteria to capture iron from the environment) https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(18)30315-X/fulltext. I am not entirely sure how far this is in clinical development, but it could work. However, as with all antibiotics, bacteria will develop resistance to these systems in the long-run (e.g. the uptake channel might mutate slightly). Other transporters are very specific for specific compounds so it might be difficult to have them take up that compound linked to an antibiotic (which is generally a fairly bulky chemical).

Great question. The crucial difference between bacteria and viruses is that viruses can only evolve resistance through mutation, but that bacteria can become resistant by mutation and process called horizontal gene transfer. So in viruses, you would be extremely unlucky if it evolves resistance to three antivirals at the same time, but in bacteria you can also have the bacterium acquiring a bit of DNA that contains resistance genes to multiple antibiotics in a single event and you would strongly select for this possibility by giving multiple antibiotics at the same time. Bacteria also have systems called efflux pumps that just pump out the antibiotics that are in the cell before they can do harm, so by giving three antibiotics simultaneously you might strongly select for bacteria with increased efflux capacity.