Herbal Antibiotics: Natural Alternatives for Treating Drug-Resistant Bacteria (4 page)

Originally limited to patients in hospitals (the primary breeding ground for such bacteria), by the 1970s resistant strains had begun appearing outside hospitals. Now they are common throughout the world's population. In 2002 I saw my first resistant staph infection outside a hospital setting. Now (2011) every month brings an e-mail or call from someone with another.

This rate of resistance development was supposed to be impossible. Evolutionary biologists had insisted that evolution in bacteria (as in all species) could come only from spontaneous, usable mutations that occur with an extremely low frequency (from one out of every 10 million to one out of every 10 billion mutations) in each generation. That bacteria could generate significant resistance to antibiotics in only 35 years was considered impossible. That the human species could be facing the end of antibiotics only 60 years after their introduction was ludicrous. But in fact, bacteria are showing extremely sophisticated responses to the human “war” on disease.

The thing that so many people missed, including my ancestors, is that
all
life on Earth is highly intelligent and very, very adaptable. Bacteria are the oldest forms of life on this planet and they have learned very, very well how to respond to threats to their well-being. Among those threats are the thousands if not millions of antibacterial substances that have existed as long as life itself.

One of the crucial understandings that those early researchers ignored, though tremendously obvious now (only hubris could have hidden it so long), is that the world is filled with antibacterial substances, most produced by other bacteria, as well as fungi and plants. Bacteria, to survive, learned how to respond to those substances a very long time ago. Or as Steven Projan of Wyeth Research puts it, bacteria “are the oldest of living organisms and thus have been subject to three billion years of evolution in harsh environments and therefore have been selected to withstand chemical assault.”
¹⁰

What makes the problem even more egregious is that most of the antibiotics originally developed by human beings came from fungi, fungi that bacteria had encountered a very long time ago. Given those circumstances,
of course
there were going to be problems with our antibiotics. Perhaps,
perhaps
, if our antibiotic use had been restrained, the problems would have been minor. But it hasn't been; the amount of pure antibiotics being dumped into the environment is unprecedented in evolutionary history. And that has had tremendous impacts on the bacterial communities of Earth, and the bacteria have set about solving the problem they face very methodically. Just like us, they want to survive, and just like us, they are very adaptable. In fact, they are much more adaptable than we ever will be.

As soon as a bacterium encounters an antibiotic, it begins to generate possible responses. This takes time, usually a number of bacterial generations. But bacteria live a lot more quickly than we do; a new generation can occur every 20 minutes for many species. This is some 500,000 times faster than us. And during that quickened time scale, bacteria have found a lot of different ways to respond to our antibiotics.

Bacteria can decrease the amount of the antibiotic that gets inside them. Antimicrobials, in most instances, need to enter bacterial cells in order to kill them—they need to negotiate the cell envelope that surrounds the bacteria. Some do this by taking advantage of the normal influx of materials that must go into the bacterial cells daily in order for them to live. In other words, they sneak in by attaching themselves to nutrients of one sort or another or even appear to be a necessary nutrient so that the bacteria take them up.

To avoid this infiltration the bacteria alter the permeability of their cell membranes, often by altering the structure of the doorways that let outside substances into the cell. This makes it harder, or impossible, for antibiotics to sneak in—essentially keeping the level of the drug below that needed to affect the bacteria.

Bacteria can alter their internal structure so that the intended target of the antibiotic won't be affected by it. As David Hooper at the Division of Infectious Diseases at Massachusetts General Hospital puts it, “Resistance by the general mechanisms of target modification can be brought about, however, by a remarkable variety of specific means, which have been exploited by different clinically important bacteria. The modification mechanism often results in an altered structure of the original drug target structure that binds the drug poorly or not at all.”
¹¹

In other words, they change the structure of their bodies so specifically that the parts of themselves that would be affected by the antibiotics aren't. The antibiotic enters the cell, but it just doesn't do anything.

Bacteria can degrade or destroy the antibiotic, even if it gets inside them, by creating antibiotic-specific inactivation or disabling compounds—often these are enzymes such as extended-spectrum beta-lactamases (ESBLs). As Harry Taber of the New York Department of Health puts it, “It is not surprising to find, then, that antibiotic inactivating enzymes are found in the [cell] envelope:
β
-lactamases and aminoglycoside-modifying enzymes are examples.”
¹²

The newest member of this group is NDM-1, New Delhi metallo-beta-lactamase. NDM-1 is a kind of ESBL but much more problematical than any known so far because it is potently active against carbapenem antibiotics, a class of beta-lactams that were previously resistant to ESBL deactivation. NDM-1 is carried on plasmids and transfers easily to a wide range of bacteria. “The frightening thing about this,” says Timothy Walsh, a professor of microbiology and antibiotic resistance at Cardiff University in the UK, is that “it appears to be spreading fast.”
¹³

Bacteria can remove antibiotics from their cells as fast as they enter them using something called an efflux pump. Essentially they create a kind of sump pump that will pump out exactly the things they want pumped out. There are a variety of efflux pumps in all bacteria, each coded for particular substances. Some efflux pumps act on only a single substance, while others (multidrug efflux pumps) can pump out a wide range of compounds. Often the compounds have very little in common with each other; no one yet understands why one pump can act on so many different kinds of substances.

But when one of those substances is identified by a bacterium, the pump kicks in, the drug goes out. Researchers have commented that these “pumps can recognize and extrude positive-, negative-, or neutral-charged molecules, substances as hydrophobic as organic solvents and lipids, and compounds as hydrophilic as aminoglycoside antibiotics.”
¹⁴

Bacteria have, over long evolutionary time, created a wide range of pump types in order to protect themselves from the millions of antimicrobial substances that exist in the world. There are five main forms:

• The major facilitator superfamily (MFS)

• The APT-binding cassette superfamily (ABC)

• The small multidrug resistance family (SMR)

• The resistance-nodulation-cell division superfamily (RND)

• The multi-antimicrobial extrusion protein family (MATE)

Most Gram-positive bacteria use MFS as their primary efflux mechanism. Most Gram-negative bacteria use RND. These pumps have a wide variety of purposes, among them the protection of the organism from things like bile salts and stomach acids, which, in their own way, act much like antimicrobials on pathogenic bacteria.

Sometimes bacteria learn how to live and prosper in antimicrobial environments, such as the cleaning solutions in hospitals. As one journal article put it, “Contamination, mainly by Gram-negative
bacteria, was found in 10 freshly prepared solutions and in 21 of 22 at discard.”
¹⁵
Sometimes, they even learn to use the antibiotics for food.

Once a bacterium develops a method for countering an antibiotic, it systematically begins to pass the knowledge on to other bacteria at an extremely rapid rate. Under the pressure of antibiotics, bacteria are interacting with as many other forms and numbers of bacteria as they can. In fact, bacteria are communicating across bacterial species lines, something they were never known to do before the advent of commercial antibiotics. The first thing they share is resistance information and they do this in a number of different ways.

Bacteria encode several different kinds of plasmids, essentially chromosome-independent DNA strands, each of which contains resistance information, and they pass these on to other bacteria. Plasmids are highly mobile genetic strands and are widely exchanged throughout the bacterial world. Aminoglycosides, for example, some of the most potent antibacterials known, were originally isolated from actinomycetes, a type of bacteria. Those bacteria created and used aminoglycosides themselves to kill invading or competing bacteria, but the aminoglycosides could also kill actinomycetes, so the actinomycetes also created something to deactivate aminoglycosides and they stored that information on plasmids inside themselves.
All
resistance to aminoglycosides worldwide, including in
Pseudomonas
and
Acinetobacter
organisms, has come from those ancient plasmids created by the actinomycetes. Once aminoglycosides began to be promiscuously prescribed by the medical community, the actinomycetes released the plasmids like a puff of dandelion seeds on the wind.

Bacteria use transposons, unique movable segments of DNA that are a normal component of their genome. Sometimes called “jumping
genes,” transposons easily move between chromosomes and plasmids. They are readily integrated into DNA structures, and when they are, the genetic makeup, and hence the physical form of the organism, is altered. Bacteria use transposons to transfer a significant amount of resistance information and often release them in free form into the environment to be taken up later by other bacteria.

They use integrons as well, a type of DNA sequence that integrates into the genome structure at specific sites. Integrons are especially active in the transfer of both resistance and virulence information.

Bacterial viruses, or bacteriophages, also help transfer resistance information between different bacteria. It is now known that instead of making only copies of themselves when they reproduce, bacteriophages take up and make copies of host chromosome segments that contain resistance information, which are then transferred to newly infected bacteria. In other words, the viruses that infect bacteria (they get colds, too) teach them how to be resistant to antibiotics.

Bacteria can share resistance information directly or simply extrude it from their cells, allowing it to be picked up later by other roving bacteria. They often experiment, combining resistance information from multiple sources in unique ways that increase resistance, generate new resistance pathways, or even stimulate resistance to antibiotics that they have never encountered before. Even bacteria in hibernating or moribund states will share whatever information on resistance they have with any bacteria that encounter them. When bacteria take up any encoded information on resistance, they weave it into their own DNA, and this acquired resistance becomes a genetic trait that can be passed on to their descendants forever—distressingly Lamarckian. Researchers have noted that the rise of resistance over the past 50 years has had a one-to-one correlation to the production and use of antibiotics and that resistance mechanisms are not just passed on to other bacteria but are conserved within species.

Antibiotics, ultimately and regrettably for us, have actions similar to pheromones; they act as chemical attractants and literally pull bacteria to them. Once in the presence of an antibiotic, a bacterium's learning rate immediately increases by several orders of magnitude. Tetracycline, in even extremely low doses—in fact, especially in low doses—stimulates from one hundred to one thousand times the transfer, mobilization, and movement of transposons and plasmids. (Treatment of acne and fattening of industrial farm animals, by the way, generally involves low doses of tetracycline, often over years.) Wendy Powell comments that “this means that in times of stress, predicated by the presence of antibiotics, the antibiotics themselves promote the exchange of plasmids, which may contain resistance genes.”
¹⁶