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The bacteria may have entered her flesh along with shrapnel from the bomb detonated in Brussels Airport in 2016. Or perhaps the microbes hitched a ride on the surgical instruments used to treat her wounds. Either way, the “superbug” refused to be vanquished, despite years of antibiotic treatment.<\/p>\n
The woman had survived a terrorist attack but was held hostage by drug-resistant\u00a0Klebsiella pneumoniae<\/em>, a bacterial strain often picked up by surgery patients in hospitals. Only by combining antibiotics with a new, experimental treatment did doctors\u00a0finally rid her of the superbug<\/a>.<\/p>\n Devastating drug-resistant bacterial infections like this one are all too common, and they represent an ever-growing threat to global health. In 2019, antibiotic-resistant bacteria directly killed\u00a0roughly 1.27 million people worldwide<\/a>\u00a0and contributed to an additional 3.68 million deaths. In the U.S. alone, drug-resistant bacteria and fungi together cause an estimated\u00a02.8 million infections and 35,000 deaths<\/a>\u00a0each year.<\/p>\n And the problem is getting worse:\u00a0Seven of the 18 concerning bacteria<\/a>\u00a0tracked by the Centers for Disease Control and Prevention (CDC) are becoming more resistant to common antibiotics\u00a0considered essential<\/a>\u00a0for maintaining public health. Meanwhile, drug companies have been slow to make new antibiotics capable of beating the microbes.\u00a0Fewer than 30 antibiotics<\/a>\u00a0currently in the development pipeline target\u00a0“priority” bacteria<\/a>, as defined by the World Health Organization (WHO), and most of those drugs are still vulnerable to resistance, just like their predecessors.<\/p>\n So some scientists are looking beyond traditional antibiotics for new weapons that won’t fuel the rise of superbugs. Their emerging arsenal features viruses that kill bacteria;\u00a0CRISPR<\/a>; and microbe-slaying molecules. They hope that these experimental treatments, some of which have been tested in patients, will kill superbugs without promoting resistance.<\/p>\n “The vision, for me, is that we move beyond antibiotics and really just see a much broader palate of options,”\u00a0Chase Beisel<\/a>, leader of the RNA synthetic biology research group at the Helmholtz Institute for RNA-based Infection Research in Germany, told Live Science.<\/p>\n But until these new therapeutics are ready for prime time, the world needs to curtail its overuse and misuse of antibiotics, which experts say is speeding up the rate at which these lifesaving drugs become obsolete.<\/p>\n Related:\u00a0<\/strong>Superbugs are on the rise. How can we prevent antibiotics from becoming obsolete?<\/strong><\/a><\/p>\n Antibiotics either\u00a0directly kill bacteria or slow their growth<\/a>, leaving the immune system to finish the job. The drugs work in several ways \u2014 by preventing bacteria from building sturdy walls or making copies of their\u00a0DNA<\/a>, for instance. Growth-slowing antibiotics usually disrupt ribosomes, the factories in which bacterial cells make proteins.<\/p>\n Many antibiotics\u00a0shoot for the exact same molecular targets<\/a>, and so-called broad-spectrum antibiotics’ mechanisms are so universal that they work on both major classes of\u00a0bacteria<\/a>: gram-positive and gram-negative, which are distinguished by the makeup and thickness of their cell walls. Broad-spectrum antibiotics, in particular, pressure both harmful and helpful bacteria in the body to\u00a0evolve defensive strategies<\/a>\u00a0that eject or disable the drugs, or else alter their targets.<\/p>\n Bacteria can pick up such defenses through random DNA mutations, or by swapping “resistance genes” with other bacteria via a process called horizontal gene transfer. By making these gene transfers, bacteria can quickly spread such mutations to additional bacterial populations in the body and in the environment.<\/p>\n The misuse of antibiotics in health care, as well as in agriculture, has given bacteria endless opportunities to develop resistance, raising the chance that once-treatable infections will become life-threatening.<\/p>\n Related:\u00a0<\/strong>New ‘concerning’ strain of drug-resistant gonorrhea found in U.S. for 1st time<\/strong><\/a><\/p>\n One of the proposed alternatives to antibiotics was\u00a0first conceived more than a century ago<\/a>, before the 1928 discovery of\u00a0penicillin<\/a>. Called phage therapy, it uses bacteria-infecting\u00a0viruses<\/a>\u00a0called \u00a0bacteriophages, or simply “phages,” which typically kill the germs by invading their cells and splitting them open from the inside.<\/p>\n Phages can also pressure bacteria into giving up key tools in their drug resistance tool kits. For example, a\u00a0phage called U136B can have this effect on\u00a0E. coli<\/em><\/a>. To infiltrate\u00a0E. coli<\/em>, the phage uses an efflux pump, a protein\u00a0E. coli<\/em>\u00a0normally uses to pump antibiotics out of the cell. If the\u00a0E. coli<\/em>\u00a0tries to change this pump to escape the phage, it reduces the bacterium’s ability to pump out antibiotics.<\/p>\n And unlike with antibiotics,\u00a0bacteria are unlikely to gain widespread resistance to phage therapy<\/a>, said\u00a0Paul Turner<\/a>, director of the Center for Phage Biology and Therapy at Yale University.<\/p>\n Turner and other experts have concluded that, “if phage therapy were used at a global scale, that it would not lead to the same problem of widespread resistance to it, the way that antibiotic use has led to that problem,” he told Live Science.<\/p>\n Here’s why: Antibiotic resistance has been dramatically accelerated by the\u00a0misuse and overuse of antibiotics<\/a>, especially\u00a0broad-spectrum antibiotics<\/a>\u00a0that work on a variety of bacteria. Phages, by contrast, can have much narrower targets than even narrow-spectrum antibiotics \u2014 for instance, targeting a protein found in only\u00a0one or a few strains<\/a>\u00a0within one bacterial species.<\/p>\n Related:\u00a0<\/strong>New drugs could stymie superbugs by freezing evolution<\/strong><\/a><\/p>\n The target bacterium can still evolve resistance to an individual phage \u2014 but by picking the right combination of phages, scientists can make it so that the bacterium’s evolution comes at a cost, Turner said. This cost might be a decrease in virulence or an increased vulnerability to antibiotics.<\/p>\n To date, phage therapy has mostly been tested through a regulatory framework known as “compassionate use” in patients like the Brussels Airport bombing victim, whose infections had no other treatment options. Phage therapy has\u00a0shown success in these settings<\/a>, and in a\u00a0recent observational study<\/a>\u00a0of 100 patients who received phages alongside antibiotics.<\/p>\n So far in clinical trials, though, phage therapy generally\u00a0hasn’t worked better than standard antibiotics<\/a>\u00a0or a placebo. Topline results from two recent trials hint at the treatment’s effectiveness in\u00a0specific lung<\/a>\u00a0and foot infections<\/a>, but the full results have yet to be released.<\/p>\n Success in future trials will be key to getting phages into the clinic, Turner said. Those trials will have to show the therapy works for multiple types of infections, determine dosage and confirm phage therapies don’t hurt helpful bacteria in the body, he added.<\/p>\n Although made famous as a powerful gene-editing tool, CRISPR technology was actually adapted from an immune system found in many bacteria: CRISPR-Cas.<\/p>\n The key components of this immune system include molecular scissors, known as Cas proteins, and a\u00a0memory bank of DNA snippets<\/a>\u00a0that a bacterium has collected from phages that once infected it. By tapping its memory bank, CRISPR-Cas can guide its lethal scissors to a precise point in an invading phage’s DNA and snip it like a piece of ribbon.<\/p>\n On occasion, though, rather than attacking phages, CRISPR-Cas can accidentally\u00a0go after the bacterial cell’s own DNA<\/a>, triggering a lethal autoimmune reaction. This phenomenon inspired Beisel and his colleagues to explore using CRISPR-Cas to shred bacterial cells’ DNA.<\/p>\n “The real draw of it is that it is a sequence-specific tool,” meaning it targets only the DNA you tell it to, and not sequences present in other bacteria, Beisel told Live Science. So, once administered to a patient, “the CRISPR machinery gets into a set of cells, but only those that have the sequence or sequences you picked will be attacked and killed.”<\/p>\n How do you get CRISPR-Cas into the right bacteria? Various research groups are testing different delivery methods, but at present, the best strategy seems to be loading CRISPR machinery into a phage that infects the target bacterium, Beisel said.<\/p>\n Related:\u00a0<\/strong>Scientists invent ‘shape-shifting’ antibiotic to fight deadly superbugs<\/strong><\/a><\/p>\n Beisel is a co-founder and scientific adviser of Locus Biosciences, a biotech company that’s currently testing\u00a0a CRISPR-enhanced phage therapy<\/a>\u00a0in a midstage, roughly 800-person trial. This approach couples the bacteria-killing prowess of phages with the ability of CRISPR-Cas to destroy essential bacterial genes. As with CRISPR-less phage therapies, clinical trials are needed to determine the treatment’s safety profile and appropriate dosing.<\/p>\n “I can see these [treatments] coming about in the five- to 10-year time frame,” Beisel said.<\/p>\n Beyond phages and CRISPR, scientists are developing antibiotic alternatives that harness bacteria-slaying peptides \u2014 short chains of protein building blocks\u2014 and enzymes, specialized proteins that jump-start chemical reactions. These molecules differ from antibiotics because they can kill a very narrow range of bacteria by targeting bacterial proteins that cannot easily gain resistance to their attacks.<\/p>\n Lab-made molecules called peptide nucleic acids (PNAs) are some of the most promising candidates. These engineered molecules can be designed to\u00a0block bacterial cells from building essential proteins<\/a>\u00a0that are crucial to their survival. PNAs do this by latching onto specific\u00a0mRNA<\/a>, genetic molecules that carry the instructions for building proteins from the cell’s control center to its protein construction sites. PNAs cannot enter bacterial cells on their own, though, so they’re\u00a0typically attached to other peptides<\/a>\u00a0that easily pass through the bacterial cell wall.<\/p>\n By targeting proteins that cells cannot change without harming themselves, PNAs can avoid triggering drug resistance, Beisel explained. The engineered molecules could also be made to\u00a0target proteins that directly contribute to antibiotic resistance<\/a>, for example, the efflux pumps used to push antibiotics out of cells or the enzymes capable of disabling the drugs. By emptying a germ’s drug resistance tool kit, PNAs can then make it vulnerable to standard treatments.<\/p>\n Antibacterial PNAs are still being\u00a0tested in lab dishes<\/a>\u00a0and animals<\/a>\u00a0and have not yet moved into human trials. And, scientists need to make sure PNA-based treatments don’t inadvertently mess with human cells or helpful bacteria.<\/p>\n Related:\u00a0<\/strong>‘Death screams’ of swarming bacteria help their comrades survive antibiotic attacks<\/strong><\/a><\/p>\n In addition to peptides like PNAs, enzymes called lysins are another promising treatment option. Lysins are used in nature by phages to split bacteria open from the inside. They act like tiny swords that slice through the outer wall of a bacterial cell, spilling its guts. The molecular sabers are\u00a0unlikely to promote resistance<\/a>\u00a0because bacteria cannot easily change the essential cell-wall components that lysins target.<\/p>\n Lysins slaughter bacteria quickly upon contact, and they can be very specific, killing some types of bacteria while sparing others. Furthermore,\u00a0lysins can be tweaked in the lab<\/a>\u00a0to change which bacteria they target, boost their potency and improve their durability in the body.<\/p>\n Some lysins have entered mid- and late-stage human trials with hundreds of participants, in which they’ve been tested as supplementary treatments to antibiotics\u00a0but garnered<\/a>\u00a0mixed results<\/a>.<\/p>\n Until these next-gen bacteria slayers make it to market, immediate measures must be taken to stall the rise of superbugs, by preventing the misuse of antibiotics that pressures bacteria to evolve resistance in the first place.<\/p>\n For example, doctors can be more diligent about confirming that bacteria, not viruses, are behind a patient’s infection before prescribing antibiotics, said\u00a0Dr. Shruti Gohil<\/a>, a lead investigator of four\u00a0INSPIRE-ASP Trials<\/a>, federally funded research aimed at improving hospitals’ antibiotic use. Other safeguards can include auditing doctors’ prescriptions to see if narrower-spectrum drugs could be used instead of broad ones, or requiring special clearance for the broadest-spectrum drugs. These steps are essential not only in hospitals but everywhere antibiotics are prescribed, from primary care to dentistry, Gohil said.<\/p>\n Each interaction between a doctor and their patient matters.<\/p>\n Gohil stressed that “by reducing individual risk, you anticipate that you will drop the overall population-level risk,” and eventually slash the prevalence of multidrug-resistant bugs.<\/p>\n Copyright 2023\u00a0<\/em>Live Science<\/em><\/a>, a Future company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.<\/em><\/p>\n<\/div>\nHow antibiotic resistance emerges and spreads<\/h2>\n
Harnessing viruses to fight bacteria<\/h2>\n
Turning bacteria’s defenses against them<\/h2>\n
Designer molecules to kill bacteria<\/h2>\n
Antibiotic stewardship can save lives, in the meantime<\/h2>\n