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The genetic basis for resistance

A Video describing The Genetic Basis for Resistance
There are two basic types of resistance. The first, is variously called innate intrinsic or inherent resistance. This is when resistance to a particular antibiotic, or group of antibiotics, is normal for a particular bacterial genus, species or entire bacterial group. It may be the result of the lack of a target for the particular antibiotic, or because that drug can’t get to its target. Examples would be vancomycin or linezolid resistance in gram-negatives. They’re resistant to vancomycin because the molecule can’t get through the gram-negative outer membrane. Linezolid is inactive because it’s pumped out of gram-negative cells.
Other examples would be resistance to aztreonam or colistin in gram-positive bacteria. And even though we think of carbapenem resistance as a high public health priority, resistance is normal in some bacterial species, such as Stenotrophomonos maltophilia.
So innate, intrinsic or inherent resistance, could be inferred if you can accurately identify your organisms to species level. Of greater public health significance, however, is acquired resistance to antibiotics. This is the type of resistance where most isolates of a bacterial species, genus, or group, would be fully susceptible to the particular antibiotic, but where resistance may arise in a few, or in some cases in many isolates. It may arise through mutation of a chromosomal gene. Examples here would be frequent mechanisms of resistance to rifampicin or ciprofloxacin. All mutation in TB, for example, which is all through chromosomal mutation.
If we think about pathogens such as the Enterobacteriaceae of a health care associated pathogens, then very often acquired resistance is because isolates have acquired new DNA making them resistant. This is an example of so-called horizontal gene transfer, horizontal spread. The typical vehicle responsible for this would be a ring of DNA known as a plasmid.
This slide summarises the major mechanisms by which bacteria can become resistant to antibiotics.
They may destroy the antibiotic. This may either be because they destroy it completely or because they modify it chemically, so that it can no longer bind to its target. They may stop the drug getting into the cell reduced uptake, often called impermeability. Or they may let the drug in but it may then get pumped out faster than it can accumulate to the critical concentrations needed to exert its antibacterial effect.
Then there are various bypass mechanisms. One particular bio synthetic pathway is blocked, but maybe a new piece of DNA encodes an enzyme that replaces the blocked pathway. An example here would be methacycline resistant in Staph aureus for example. And finally, bugs can become resistant to an antibiotic because they overproduce a target enzyme and so swamp the antibiotic.
Bacteria don’t keep resistance to themselves, particularly if that resistance is mediated by plasmids. Resistance due to chromosomal mutation can overly be spread if the organism with that mutation spreads. But if resistance is on a plasmid, the plasmid can move. On the left of this slide, you see an electron micrograph of two cells of the gut bacterium Escherichia coli The top one is a recipient. The bottom one is a donor. The donor will have a resistance plasmid that the recipient lacks. You can see them being linked through a protein tube known as the sex pilus. Through a process that’s not entirely understood, the donor will give away a copy of its resistance plasmid to the recipient.
So you then end up with two cells that have the resistance plasmid and the recipient becomes a donor, able to transfer its resistance plasmid on still further. This mating event happens most effectively when the bacteria belong to the same species, but they could belong to the same genus, the same family, and in some cases bacteria can spread their resistance to completely unrelated bacterial species. So as an example, a resistance that emerges initially the E. coli may appear subsequently klebsiella, enterobacter, and a range of other bacteria. This is summarised in the cartoon on the right of the slide, where one bacterium is being offered a piece of DNA that will make it resistant to penicillin.
Plasmids are rings of DNA that exist in its bacterial cell outside of the chromosome. They may be very small and encode no resistance genes. They may be very big and encode very many resistance genes. It’s a system that has evolved and from our perspective these plasmids may often be viewed as neat packages of multi-resistance. Acquisition of a single molecule can make a bacterium resistant to many different types of antibiotics.
That’s shown here on this table, a plasmid that confers resistance to eight different classes of antibiotics. You can see that even within a particular class B-lactams, aminoglycosides, this plasmid contains more than one gene responsible for resistance. And in the final column, you can see that this also represents many of those resistance mechanisms, modifying the drug, destroying the drug, actively effluxing the drug from the cell, or providing bypass mechanisms to overcome enzymes that are inhibited.
Resistance is inevitable and entirely natural. It’s a response by bacteria to adverse growth conditions. Unfortunately, resistance is also inevitable even to new antibiotics.
Drug companies developing a new antibiotic will consider how easy it is to make bacteria resistant to their new antibiotic. What they really want to know is where the resistance is going to emerge quickly. In the particular target species, and especially, is that resistance likely to be transferable.
If it’s mutational, then control of the resistant strains, if they emerge, will limit the spread of the resistance. If it’s a transferable resistance mechanism on one of these plasmids, then potentially it becomes far more difficult to contain. Ideal scenarios that every pharmaceutical company would love to meet for any new antibiotic are illustrated at the bottom of the slide. Penicillin resistance just doesn’t happen. In beta-hemolytic streptococci, such a Strep pyogenes. Even though we’ve been using good old penicillin for over seventy years, there are no substantiated cases of resistance. And no one can explain why. Vancomycin resistance also took an awful long time to emerge, almost 30 years, although for much of this time it wasn’t being used widely.
So resistance is inevitable.
Don’t believe the spiel if the drug company reps tell you that resistance to their new antibiotics is impossible. As you will read in the text supplied for this week of the MOOC, bacteria have been on the planet for over three billion years. In that time they have evolved to overcome many adverse growth conditions, antibiotic exposure is just one of those. They respond, they become resistant, and potentially cause clinical problems.
The forensics of antimicrobial resistance therefore, involves many different levels. Best understood as a pyramid. A concept first proposed to me by my colleague, Rafael Canton from Spain. Resistance involves the emergence of mutations, the spread of resistance genes, and the spread of resistant strains.
And so clinical microbiologists reference laboratories are interested in characterising and tracking these strains and the genes that make them resistant to antibiotics. At the peak of the pyramid, you have the resistance genes that encode the enzymes. Then you have to consider what those genes are located on, the genetic carriers, which may be plasmids. Then you have to consider what’s causing an infection, which is a host bacterial species, what strain, what clone, how virulent is it, and what other drugs is it resistant to. And finally of course, you have the patients from whom you’re isolating these resistant bacteria. Are they in a hospital setting? Are they in a community setting? Are they in both?
And what are the risk factors for acquiring a resistant organism, as compared with a susceptible organism. All of these things, put together, give a far better understanding of the epidemiology of antibiotic resistance.

In this video Prof Neil Woodford describes the mechanisms of resistance in bacteria giving an overview of the types of resistance. He also considers whether resistance is inevitable.

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Antimicrobial Stewardship: Managing Antibiotic Resistance

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