Can you design a bacteriophage that attacks the part of the bacteria that makes them antibiotics resistant?

Question

I read in a newspaper about a case where they had found a virus that could attack a specific form of antibiotics-resistant bacteria and managed to save a girl from a certain death by "infecting her" with the virus.

See this article for instance.

I would like to know if it is possible to construct a virus that attacks the part of the bacteria that makes them immune to antibiotics?

I mean if you could combine a certain type of antibiotics with a virus that attacks any bacteria that is immune to that particular type of antibiotics the bacteria is in a bad place.

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I have read before, now citing this answer

"Bacteria usually gain resistance mechanisms through horizontal gene transfer (such as conjugation and phage infection)."

and that bacteria can be resistent by for instance:

"produce beta-lactamase that inactivate many lactam based antibiotics such as penicillin."

then if you can construct a drug that somehow can attack the bacteria because of the specific genetic code that gives the bacteria the ability to produce beta-lactamase then you might be able to attack all bacteria that shares the same genetic code that gives them that ability and the bacteria can not mutate to escape without losing their resistance to penicillin.

Answer 1

Check out phage therapy. For more details check out the reviews by Levin & Bull (2004) and Skurnik & Strauch (2006). The idea was around for quite some time and there is active ongoing research in this field.

However, this idea just involves killing the bacteria using bacteriophages and not reducing their resistance to antibiotics. The bacteria that are immune to antibiotics can be killed by viruses (and vice versa). If you use them in combination then possibly there can be synergistic effects under a certain regime.

Another clinical trial was conducted to evaluate a combination of the antibiotic enrofloxacin and intramuscularly administered bacteriophage (Huff et al., 2004). Both treatments individually provided effective treatments of the E. coli infection, but the synergy between the two treatments led to a total protection of the birds, thus suggesting a significant value of the combined treatment.

^{Skurnik & Strauch (2006)}

The combined treatment may not always be synergistic; they could also be antagonistic and therefore a good therapeutic strategy should be applied (Chaudhry et al., 2017).

As suggested above for tobramycin, antibiotics can be antagonistic to phage because they reduce the density of the bacteria and thus the capacity of these viruses to replicate [43]. Worse, antibiotics may even interfere with phage replication within the cell, thereby causing a reduction in phage numbers [41, 44, 45]. One way to test the effects of this possible antagonism is to treat with phage first and subsequently treat with the antibiotic, comparing the outcome with the case of simultaneous treatment. Here, we used delays of 4 and 24 hours. Results show substantial effects of delayed treatment with phage for some antibiotics but no effect for others (Fig 4). The only statistically significant effects of delay are for the 24 hours delay using gentamicin and tobramycin, but the magnitude of the effect is profound. These are two of the three drugs for which simultaneous treatment suppressed phage replication (Fig 4B). The third such drug that suppressed phage replication with simultaneous treatment (ciprofloxacin) also exhibited greater kill with phage-first treatment, but the statistics fail to reject the null hypothesis of no effect of delay. This case warrants further investigation.

Unfortunately, bacteriophages are very host-specific and are hence not as broad spectrum as antibiotics. They are just like viruses of animals: the virus that infects a cat would most likely not infect humans. Very few viruses have a broad range of hosts.

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For your query:

if you can construct a drug that somehow can attack the bacteria because of the specific genetic code that gives the bacteria the ability to produce beta-lactamase then you might be able to attack all bacteria that shares the same genetic code that gives them that ability and the bacteria can not mutate to escape without losing their resistance to penicillin.

the answer is that it is possible in principle. There are ways to knock out certain genes (CRISPR-Cas is one of the ways). However, the problem is the delivery of these molecules that mediate these knockout, to the bacterial cells. For that, you again have to rely on virus like particles for the delivery which gets us back to square one: how to make delivery machines/viruses that target all pathogenic bacteria. Moreover, the mechanisms of antibiotic resistance are diverse. Considering several other factors (that I am not going to list here), it is very difficult to make an efficient system for targeting antibiotic resistance genes in different bacteria.

Answer 2

It's possible and certain engineered solutions might be even more potent than just phage therapy on its own. For example, imagine if you could deliver CRISPR-Cas with a lysogenic bacteriophage (that is, the phage delivers a CRISPR-Cas payload, and that payload gets integrated into the host genome without immediately killing the bacteria). The CRISPR-Cas system could then activate expression, and maybe not edit genes, but let's say down-regulate specific known antibiotic resistance genes or programs, this is known as CRISPR interference. This regulation could be done to the antibiotic resistance bacteria, and then followed up with antibiotics, resulting in much higher efficacy of treatment. It's like a Trojan horse! Researchers recently have even begun to scale this sort of CRISPRi program to target many genes simultaneously and have demonstrated how this approach could reduce bacteria "survivors" (referred to a persisters by the field) by more than an order of magnitude following treatment of antibiotics such as ampicillin, ofloxacin and cefixime (Reis et al., 2017).