Drug resistance specter is fact of life for antibiotics

In the justified worries about drug resistance, it tends to get somewhat lost that there is, as yet, no completely untreatable superbug. The colistin resistance gene mcr-1 that was detected on plasmids in China and Europe in 2015, and in the US in 2016, has not yet met up with a bacterium that is resistant to all other drugs.

With the discovery of the plasmid containing mcr-1, though, a completely untreatable bug now looks to be inevitable sooner rather than later.

At this point, the infectious disease world is "just waiting – hopefully for a long time" for the mcr-1 plasmid to find its way into a strain of carbapenem-resistant Enterobacteriaceae (CRE), creating a truly untreatable superbug, Karen Bush, professor of practice in biotechnology at Indiana University, told the audience over the weekend at the 2016 annual meeting of the American Society for Microbiology (ASM) Microbe in Boston.

In the meantime, there are plenty of bugs that may not be completely resistant to everything, but are resistant enough to kill those infected with them. According to the Centers for Disease Control and Prevention (CDC), in the U.S., 23,000 people a year die of drug-resistant infections.

In a Review on Antimicrobial Resistance, also known as the O'Neill report, commissioned by the U.K. Government and the Wellcome Trust and published in May of 2016, the authors estimated that by 2050, antimicrobial resistance could directly cause 10 million deaths globally – easily outstripping heart disease, which according to the WHO is the current top cause of death, accounting for 7.4 million deaths in 2012.

For now, "even in the current situation, we have huge medical issues that are not dealt with," Robert Hancock, professor of microbiology and immunology at the University of British Columbia, said at the ASM Microbe meeting.

Those issues include sepsis, for which antibiotic is the backbone of treatment and which has a 30 percent mortality rate, and serious burns, whose victims which often die of infections.

To top it off, a loss of effective antibiotics would have a ripple effect on much of modern medicine. In the absence of antibiotics, many medical conditions procedures that are now serious but routine, including injuries, premature birth, cancer chemotherapy, and surgery, would turn into a sort of medical Russian roulette.

There is broad consensus that at least with antibiotics that work by killing bacteria, resistance is the ultimate fate of any antibiotic.

In its 2014 report on the current status and future directions of its antibacterial resistance program, the National Institute of Allergy and Infectious Diseases (NIAID) noted that fundamentally, antibiotic resistance "is an inevitable outcome of the evolutionary principle that organisms will mutate to escape lethal selective pressure. As long as we use antibiotic agents designed to kill bacteria, antibiotic resistance will continue to emerge."

Not everyone agrees with this assessment. Kim Lewis, director of Northeastern University's Antimicrobial Discovery Center and the discoverer of teixobactin, (see the related story in this issue), said at the ASM meeting that "the dogma we have been operating under, that resistance is always going to develop, and develop rapidly, may be incorrect."

Lewis' opinion was a minority report, though. Karen Bush, professor of practice in biotechnology at Indiana University, who followed Lewis' talk with an overview of the current antibiotics pipeline, said that in her opinion, "eventually we will see resistance" to any antibiotic.

Lewis' opinion is based on the fact that teixobactin's targets are not proteins, but lipid components of the cell wall, which means that resistance cannot develop by way of a single mutation. Furthermore, the drug does not need to enter cells to be effective, which means that bacterial efflux pumps, which are one of the most formidable barriers to antibiotic effectiveness, are useless against the drug.

BEATING THE UNBEATABLE

Bacteria, though, have found ways to beat supposedly unbeatable drugs before.

"When I was a grad student, people said you will never see resistance to vancomycin," an antibiotic which targets a complex part of the bacterial cell wall, Spero Therapeutics Inc. executive director of early drug discovery Michael Pucci told BioWorld Today. Vancomycin resistance enterococci (VREs) are now among the more frequent hospital-acquired infections.

For drug discovery, whether resistance is inevitable does not matter in a practical sense.

"We take a different perspective as drug developers," Spero CEO Ankit Mahadevia told BioWorld Today. "We have to assume that resistance may be a possibility."

And "whether we assume that resistance will be a big or a small problem, we have to generate the data" to understand possible mechanisms that may mediate resistance to any drug in development.

Drug resistance is a problem with interlocking scientific, financial and public health aspects. Currently, neither scientific research nor political will are keeping up with the pace at which resistance is becoming a public health problem.

In principle, though, there are a number of scientific approaches to drug development that can slow the development of resistance. And slowing down resistance tips the race between losing existing drugs to resistance and developing new ones in favor of the latter.

MUTATE, ALTER OR INACTIVATE

Broadly speaking, bacteria have three ways of developing resistance to drugs. They can mutate the target of an antibiotic, alter drug access to the target, or inactivate the drug.

In practice, most drug-resistant bacteria use combinations of the three.

One way of finding new drugs for resistant bugs is to expand the search into what Lewis calls "the microbial dark matter" – the 99 percent of bacteria that cannot be cultured with what is still the standard method of growing them on nutrient media in a petri dish, and are likely to have other ways of dealing with their fellow bacteria in addition to those biomedicine has already discovered.

Lewis has developed the Ichip, a method which can culture an estimated half of all bacteria, and used it to discover teixobactin, which is in preclinical development by startup Novobiotic Pharmaceuticals Inc. (See the related story in this issue.)

Combination therapies can be helpful both for restoring or extending the efficacy of drugs, and for slowing the development of resistance by reducing the antibiotic dose that is given as part of a combination regimen, enabling better stewardship of existing drugs.

One of the most mature approaches to combination therapy is the beta-lactamase inhibitors.

Beta-lactams are a large class of antibiotics that includes penicillin derivatives, cephalosporins and carbapenems. A common way for bacteria to develop resistance is by acquiring a beta-lactamase, an enzyme that destroys the antibiotic. There are many different beta-lactamases, and by now, there is a cottage industry of inhibitors in all phases of clinical development that aim to restore the beta-lactam's efficiency by preventing the bacterium from chewing it up.

Earlier this month, Allecra Therapeutics GmbH raised €22 million (US$24.7 million) in a series B round to fund phase II trials for AAI202, a combination of a beta-lactam antibiotic together with a proprietary, extended-spectrum beta-lactamase (ESBL) inhibitor designed to treat gram-negative multidrug-resistant infections. (See BioWorld Today, June 16, 2016.)

LOCATION, LOCATION, LOCATION

Another example of combination therapy is Spero's SPR741, which targets the outer cell membrane of gram-negative bacteria.

In general, the development landscape for gram-negatives is grimmer than that for gram-positives, partly because gram-negatives have an additional cell membrane that makes it that much tougher for drugs to get into them.

Resistance to gram-negatives is the more alarming clinical problem, because even drugs that are specifically meant to address emerging resistance threat have little activity in gram-negatives. If successful, SPR741could help both new and existing drugs to be effective across a broader swath of bacterial foes.

FOCUS!

A good bit of bacteria resistance is a bystander phenomenon that is rooted in antibiotics' broad-spectrum activity. Many bacteria, including Escherichia coli and, the Enterococci, and Staphylococcus aureus, are commensals and become a problem only when they are a cross the body's defenses and become systemic, which in turn happens mostly in already ill or immunocompromised patients.

With broad-spectrum antibiotics, each course of antibiotics affects the commensal microbiome as well as the infection it is meant to treat, making it more likely that if a commensal does manage to cause a systemic infection, that commensal will be a drug resistant one.

Wiping out the microbiome can also open up a niche for troublesome bacteria, allowing bad actors such asClostridium difficile, the bug responsible for most hospital-acquired cases of recurrent diarrhea, to gain a foothold.

Narrow-spectrum agents often face a clinical challenge because many diseases, such as pneumonia, can be caused by several different bacteria, and treatment needs to be initiated immediately, before the exact offender can be identified. Culturing bacteria to see what exactly a patient is infected with takes days; in severe sepsis, the most extreme example, every delay of one hour in therapy raises the mortality rate by seven to eight percent. (See BioWorld Today, Sept. 22, 2015.)

As a result, narrow-spectrum drugs will be successful only in those cases where the offending bacterium is known, or a rapid diagnostic exists. At the ASM meeting, Carey-Ann Burnham, associate professor of pathology & immunology at Washington University School of Medicine, told the audience that "my holy grail" would be to be able to identify the precise cause of an infection within five hours.

Within their constraints, narrow-spectrum agents are making progress, in particular the body's own infection-fighting narrow-spectrum agent of choice – antibodies.

In June, the FDA's Antimicrobial Drugs Advisory Committee voted to recommend the antibody bezlotoxumab (Merck & Co Inc.) for the prevention of C. difficile infection.

If approved, bezlotoxumab will join Medimmune's Synagis, approved to treat RSV infection, as the second approved anti-infective antibody.

Medimmune also has two antibodies in clinical trials, MEDI4893, which targets Staphylococcus aureus, and MEDI3902, which goes after Pseudomonas aeruginosa. Both bugs are so-called ESKAPE pathogens, a group of six pathogens that have been highlighted by the Infectious Diseases Society of America as drug-resistant organisms that need to be most urgently addressed.

Genentech Inc. is using antibodies to deliver antibiotics intracellularly, a twist on the antibody-drug conjugates being used in cancer therapy. In 2015, the company reported preclinical data showing that an antibody-antibiotic conjugate was able to enter cells and kill intracellular S. aureus, a reservoir for relapsing infections.

Other narrow-spectrum approaches include turning the tables on bacteria by infecting them with bacteriophage viruses – an approach that is early stage but was highlighted by the NIAID in its 2014 report as a promising approach to the treatment of drug-resistant infections.

DON'T KILL THE MESSENGER

Both MEDI4893, which targets S. aureus' alpha toxin, and bezlotoxumab are also examples of another approach that lowers the risk of resistance, namely, virulence factor targeting.

"We're trying to kill the bacteria," Jennifer Martin, an investigator at the University of Queensland's center for superbug solutions, told the audience at the ASM Microbe meeting. "But the reason we're doing that is because they produce all sorts of virulence factors" including toxins, poisons, quorum sensing molecules, adhesion and motility proteins.

At the ASM meeting, Martin described the enzyme DsbA as a master virulence regulator that could be another target for this approach.

Virulence targeting, too, has its drawbacks, including the fact that the ability to demonstrate cell-killing activity is still a cornerstone of the FDA's antibiotic approval process, and the fact that bacteria that do develop resistance to an anti-virulence agent can run rampant in the absence of a bactericidal agent. But the approach would not induce the massive selective pressure for antibiotic resistance that comes with bactericidal antibiotics.

One approach to killing bacteria is to ignore them and target the host immune system instead. At the ASM Microbe meeting, UBC's Hancock gave an overview of such approaches, which are being developed as adjunct treatments to antibiotics.

Hancock was with the majority with his assessment of the effect those approaches would ultimately have. "I'm a microbiologist," he said. "I have huge faith in resistance occurring regardless of what we think."

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