New type of decoy drug can tackle infections that are resistant to antibiotics


Imperial medical students have helped to devise a new type of ‘decoy’ drug to tackle infections that are resistant to antibiotics.

In lab tests on bacterial cultures, the new drug successfully killed a strain of drug-resistant bacteria.

It works by delivering two antibiotics, one of which is effectively hidden. When the bacteria fight against the first ‘decoy’ antibiotic, this action opens up the drug, triggering the second antibiotic into action.

This enables the second antibiotic to be delivered in a targeted way, only being released where it encounters drug-resistant bacteria.

The findings could help prolong the life of existing antibiotics by slowing the rate at which bacteria become resistant to them.

Antibiotic resistance is a growing problem worldwide, with microbes evolving ways to avoid being killed by a range of medications.

It is impacting the fight against TB, HIV and malaria, as well as threatening the success of major surgery and cancer chemotherapy.

Now, researchers at Imperial College London have designed a new way to deliver antibiotics that only targets and kills bacteria that have evolved a mechanism of resistance to frontline antibiotics.

Any remaining infection caused by non-resistant bacteria can be cleared using normal penicillin.

Their results are published in the Journal of Medicinal Chemistry.

Setting a trap

A wide range of bacteria, including E. coli, have evolved a special enzyme that can cleave (split) frontline antibiotics known as cephalosporins, rendering them useless.

The combined drug (pro-drug) is activated by bacteria containing the enzyme beta-lactamase, which can cleave cephalosporins. Credit: Imperial College London

The cephalosporins are a family of bactericidal antibiotics structurally related to penicillin which were first derived from the fungus, Cephalosporum acremonium. 

Their basic structure is similar to penicillin with a thiazolidine and beta-lactam ring, which has a variable side chain. 

Cephalosporins bind to the penicillin-binding proteins on bacteria and inhibit synthesis of the bacterial cell wall, causing cell lysis particularly in rapidly growing organisms. 

Their differences in activity relate to the range of penicillin-binding proteins that they inhibit. 

They have a broader activity than the standard penicillins, but are also sensitive to some extent to beta-lactamase. 

Five generations of cephalosporins have been developed with varying antibacterial activity. 

Cephalosporins are indicated for infections with susceptible organisms. 

Cephalosporins have variable oral absorption and many must be given parenterally.  In the lists below, formulations that are available in oral and parenteral forms are shown separately.

First generation cephalosporins include cefadroxil, cefazolin, cephalexin, and cephradine, and these are active against many gram-positive cocci, including penicillinase-producing Staphylococcus aureus.

Second generation cephalosporins include cefaclor, cefoxitin, cefprozil, cefonicid, and cefuroxime; these have broader antibacterial activity, and additional sensitive organisms including Citrobacter, Enterobacter, Haemophilus influenzae, Neisseria and Serratia species.

Third generation cephalosporins include cefdinir, cefditoren, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone, which are less active than first- and second generation drugs against gram-positive bacteria, but more active against gram-negative organisms and have greater stability against beta-lactamases.

Fourth generation cephalosporins include cefepime, which are active against a wide range of both gram-positive and gram-negative organisms.

Fifth generation cephalosporins include ceftaroline and ceftolozane/tazabactam,  which are active against a wide range of both gram-positive and gram-negative organisms including methicillin resistant Staphylococcus aureus (MRSA).  These agents are sometimes referred to as advanced generation rather than fifth generation cephalosporins. 

Cephalosporins have side effects similar to penicillin, and drug-allergy and hypersensitivity are often (but not always) shared. 

The cephalosporins in general have been associated with little hepatotoxicity and only rare instances of drug induced liver injury due to these agents have been published. 

A special exception is ceftriaxone, a third generation cephalosporin which, when given parenterally, can cause biliary sludge with symptoms of cholecystitis and cholestatic jaundice. 

For these reasons, other than for ceftriaxone, the cephalosporins will be discussed as a general class rather than individual agents, and separately for the intravenous and oral forms. 

The cephalosporins are assigned a likelihood score of causing clinically apparent liver injury as a class.  Some have been implicated in only a few cases, but in general the liver injury from cephalosporins is similar from case to case. 

The typical case of liver injury from cephalosporins is a self-limited cholestatic hepatitis with mild if any immunoallergic features that arises 1 to 3 weeks after starting therapy, sometimes occurring after a single parenteral dose.

Oral CephalosporinsCefaclor (2nd)Cefadroxil (1st)Cefdinir (3rd)Cefditoren (3rd)Cefixime (3rd)Cefpodoxime (3rd)Cefprozil (2nd)Ceftibuten (1st)Cephalexin (1st)Cefuroxime (2nd)Cephradine (1st)Loracarbef (2nd) Parenteral CephalosporinsCefazolin (1st)Cefepime (4th)Cefoperazone (3rd)Cefotaxime (3rd)Cefoxitin (2nd)Ceftaroline (5th)Ceftazidime (3rd)Ceftibuten (3rd)Ceftizoxime  (3rd)Ceftolozane/Tazobactam (5th)Cefuroxime (2nd)Cephradine (1st)Ceftriaxone (3rd)

To get around this, the team attached a cephalosporin molecule to a secondary antibiotic called ciprofloxacin.

When resistant bacteria encounter the combined drug they cleave the cephalosporin, setting the ciprofloxacin free to kill the bacteria.

Ciprofloxacin is rarely used as a primary treatment for infections because it can have severe side effects.

However, since it is only activated when the cephalosporin is cleaved, the levels in the bloodstream are much lower and will hopefully lead to fewer side effects.

Co-author Dr. Thomas Webb said: “No matter how good bacteria are at evolving resistance to antibiotics they can never ‘think ahead’, and this is why we believe setting a trap for them in this way may be so effective.”

Fighting resistance

Antibiotic resistance often emerges because drugs are used indiscriminately against any infection, without knowing its specific cause.

This method targets the weakest bacteria, leaving the strongest bacteria to survive and pass on their genes for resistance.

However, the new drug is more specific, targeting only already-resistant bacteria.

Clearing the body of antibiotic-resistant bacteria is particularly important when patients have repeat infections, as it’s likely these resistant bacteria are hiding out in the body between symptomatic episodes.

For example, urinary tract infections, some of the most common infections in the world, are often caused by resistant bacterial populations persisting in the body.

Clearing the body of resistant bacteria would also be useful prior to surgery or chemotherapy, to prevent opportunistic infections while the body’s immune system is compromised.

Because of its targeted nature, the new drug combination is also predicted to be gentler on the body’s microbiome—the ecosystem of bacteria that naturally live within our bodies and can help fight infections.

New uses for old drugs

The team have applied for a patent for their drug and are working on expanding the concept to other antibiotics.

Lead researcher Dr. Andrew Edwards, from the MRC Centre for Molecular Bacteriology and Infection at Imperial, said: “Given the lack of new drugs in the pipeline it’s essential to develop new ways of using the existing stock of effective medicines to function in new ways, to reduce their damaging effects on our resident ‘good bacteria’ and to slow the rate at which bacteria become resistant to them.”

Dr. Thomas Webb and Dr. Dominic Marshall came up with the concept in 2013, when they were first-year medical students at Imperial. They worked with Professor Alan Armstrong in the Department of Chemistry and Dr. Andrew Edwards in the MRC Centre for Molecular Bacteriology and Infection at Imperial to develop the idea, funded by an Imperial Confidence in Concept award.

After an initial prototype was successful, Dr. Lindsay Evans, an EPSRC-funded EMBRACE fellow picked up the baton and worked with the research team to secure funding from the Wellcome Trust to develop the idea further, along with Dr. Jim Spencer from the University of Bristol.

More information: Lindsay E. Evans et al. Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug, Journal of Medicinal Chemistry (2019). DOI: 10.1021/acs.jmedchem.8b01923
Journal information: Journal of Medicinal Chemistry
Provided by Imperial College London


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