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How do bacteria destroy antibiotics?

Dr Rosssana Rosa
In this video, we will explore the basic types of bacterial resistance. The first type of resistance is called intrinsic or inherent. This occurs when resistance to a particular antibiotic or group of antibiotics is normal for a particular bacterial genus, species, or an entire bacterial group. This may be the result of the lack of a target for the particular antibiotic or because that drug can’t get to its target. Some examples of this type of resistance are vancomycin or linezolid resistance in gram negatives. This occurs because the molecule can’t get through the gram-negative outer membrane. Linezolid is inactive because it’s pumped out of gram-negative cells.
Now acquired resistance is a type of resistance where most isolates of a bacterial species, genus, or group start by being fully susceptible to the particular antibiotic. But resistance may arise in a few, or in some cases, many of their isolates. This resistance may arise through mutation of a chromosomal gene. An example of this is an enterobacteriaceae, which often develop resistance by acquiring new DNA. This is an example of so-called horizontal gene transfer, or horizontal spread. The typical vehicle responsible for this would be a ring of DNA known as a plasmid. We will now watch a video by Professor Neil Woodford who explains the major mechanisms by which bacteria can become resistant to antibiotics.
[AUDIO PLAYBACK] - 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 biosynthetic pathway is blocked. But maybe a new piece of DNA encodes an enzyme that replaces the blocked pathway. An example here would be methicillin resistance in staph aureus, for example.
And finally, bugs can become resistant to an antibiotic because they over-produce 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 only 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 a 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 in E. coli may appear subsequently in klebsiella, enterobacter, and a range of other bacteria. And 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 this 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 bacteria 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, beta 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 whether 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 70 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 anti-microbial 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 the infection, which is a host bacterial species. What strain? What clone? How virulent is it? And what other drugs is it resistant to? 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. [END PLAYBACK]

Antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial medicine to which it was previously sensitive. Resistant organisms (which include bacteria, viruses and some parasites) are able to withstand attack by antimicrobial medicines, such as antibiotics, antivirals, and antimalarials, so that standard treatments become ineffective and infections persist and may spread to others.

In this video Dr Rossana Rosa explains the two types of resistance.

Incorporated into this video is a section created by Prof Neil Woodford for the Antimicrobial Stewardship: Managing Antimicrobial Resistance course which explains the mechanisms by which bacteria become resistant.

You can download the slides for both sections of the video here and at the bottom of the step.

Hands with surgical gloves holding two petri dishes growing bacteria Image CDC/ James Gathany

This image shows two petri dish culture plates growing bacteria in the presence of discs containing various antibiotics. The isolate, i.e. bacterial species, on the left plate is susceptible to the antibiotics on the discs, and is therefore unable to grow adjacent to the discs. The plate on the right was inoculated with a Carbapenem-Resistant Enterobacteriaceae (CRE) bacterium that proved to be resistant to all of the antibiotics tested, and is therefore able to grow near the discs.

You may also like to watch this video The Animation of Antimicrobial Resistance by Medicanon which also explains how bacteria become resistant to antimicrobial chemotherapy.

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Challenges in Antibiotic Resistance: Gram Negative Bacteria

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