Will all bacteria become resistant against all antibiotics in the long term?

Question

(I asked the same at medicalsciences beta, but I expect a quite different perspective on it here)

This is about bacteria that can infect humans, and their multi-resistance.

The evolution of bacteria to be resistant against antibiotics is certainly a trait that is helpful for the bacteria, and there is not much evolutionary pressure to loose it. We will always hope that the next best antibiotic will help against a given infection, giving the bacteria a chance to get immune against the next as soon as we lost the battle for the previous one.

Does that deterministically add up to all bacteria being resistent against all antibiotics in some point in time?

Or is there reason to assume that we can find new antibiotics fast enough to outrun bacteria evolution? I assume it's not, because evolution will not stop, and there is a finite number of antibiotics, I would expect.

(Or is there reason to believe that we become extinct before all bacteria become resistant, so we do not need to worry about bacteria?)

Answer 1

and there is not much evolutionary pressure to loose it

The energetic cost of replicating antibiotic resistance genes in the absence of antibiotic selection is not trivial, and varies depending on the environment and genetic background of the strain.¹ Beyond simple metabolic costs, there is some recent research that suggests that carriage of resistance genes in the absence of antibiotic selection leads to more frequent DNA breaks, adding a mutational burden to resistant strains.²

It may also be the case that expression of a resistance gene by one cell affords a protective phenotype to neighboring cells. Consider β-lactams, the most common class of antibiotics. Resistance to β-lactams is often achieved by secretion of β-lactamases, so genetic heterogeneity of a bacterial population can be maintained with respect to β-lactamase gene carriage as long as the cells with the gene are producing sufficient enzyme to protect their susceptible neighbors.

Or is there reason to assume that we can find new antibiotics fast enough to outrun bacteria evolution? I assume it's not, because evolution will not stop, and there is a finite number of antibiotics, I would expect.

Then why not use evolution to our advantage? Phage therapy is a field that has been around for decades, but there has been a resurgence of interest as the frequency of infections by multidrug-resistant pathogens increases. Because phages parasitize bacteria, the effective sequence space for phage evolution is as large as the sequence space for bacterial evolution, and equally fast. Phage therapy has been highlighted recently for its ability to eliminate infections that are recalcitrant to antibiotic treatment.³ Interestingly, phage selection can be used in conjunction with antibiotic treatment to re-sensitize resistant bacteria to antibiotics.⁴

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1. Durão P, Balbontín R, Gordo I. Evolutionary Mechanisms Shaping the Maintenance of Antibiotic Resistance. Trends Microbiol. 2018 Aug;26(8):677-691.
2. Balbontín R, Frazão N, Gordo I. DNA breaks-mediated cost reveals RNase HI as a new target for selectively eliminating antibiotic resistance. bioRxiv. 2020.
3. Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, Gilmour KC, Soothill J, Jacobs-Sera D, Schooley RT, Hatfull GF, Spencer H. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019 May;25(5):730-733.
4. Chan BK, Sistrom M, Wertz JE, Kortright KE, Narayan D, Turner PE. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci Rep. 2016;6:26717.

Answer 2

As mentioned, antibiotic resistance is actually quite expensive. Bacteria that fail to discard it when antibiotics are not present will be wiped out by competition from other bacteria that devote more resources to reproduction.

One major source of antibiotic resistance is the 'multidrug efflux pump' which transports harmful chemicals outside the cell. You can imagine how it costs energy to run a pump. These pumps also protect the cell from other harmful molecules such as heavy metals and organic pollutants, so making them more specialized for antibiotics will increase vulnerability to other toxins.

Looking at the question more broadly, if bacteria could become universally resistant, it would have happened already. Remember that the most famous antibiotic, penicillin, was discovered because a fungus invaded and killed bacteria being cultured in a petri dish. The microbiological world is a brutal war that has raged constantly for billions of years between bacteria, phage, fungi, other bacteria, etc. Antibiotics and the resistance to them have been around much longer than humans, let alone modern medicine. If we don't take that into account, it seems like medically important pathogens have developed new defences in a very short time, so we overestimate their ability to adapt to new threats.