Herbal Antibiotics: Natural Alternatives for Treating Drug-Resistant Bacteria (34 page)

In spite of this, Western herbalists as a group have nearly no understanding of synergy in plant medicines. Those few that do have some sense of it tend to speak of it in such vague terms that the concept is virtually useless. Part of the problem is simply that the concept hasn't had any developed presence in the herbal literature. It is hard to think about something you have never heard about. Another very common problem is the fear of sounding too “New-Agey” or “airy-fairy”—translation: not “scientific” enough. Herbalists, like all other people on the planet, do want to be accepted by their culture; the pervasiveness of such a widespread reductionist paradigm has had the (often intended) effect of causing people to censor their own thoughts. Thus the long-term herbal mimicry of the monotherapy paradigm in both the United States and Europe that has had such a tenacious and negative influence on the field.

More deeply problematical, the majority of Western herbalists simply have not spent much time developing
their own
particular in-depth understanding of plant medicines, nor have they trusted themselves enough to support the modern development of
their own
unique system—a system that has very old roots in numerous indigenous cultures in the Americas, the older European cultures (Greek and Roman, for instance), and that of community herbalists nearly everywhere. Instead, most have mimicked older systems (TCM, for instance) or taken on the trappings of the newer system of technological medicine. They have spent decades trying to force their unique Western system, a system of which they have some sense every day of their lives, into those forms. (The American herbalist Michael Moore was a major exception to that trend.) Square peg into round hole living. It is time to
own
our own unique system, without embarrassment, without pretending or trying to be what we are not.

There are many aspects to our emerging Western herbal paradigm that need to be developed in depth; one of those is the understanding of plant synergy. This chapter is an early beginning, however brief or incomplete, in attempting to address it.

In the sense I am using the concept here, plant synergists act to increase the activity of other plants used for healing while affecting the body itself through a number of other, supportive actions. They do this through a wide range of mechanisms:

• They act to reduce toxic side effects of primary constituents.

• They increase depth and broadness of constituent penetration by among other things increasing intracellular transport.

• They enhance constituent activity by acting at different points of the same signaling cascade.

• They decrease the effective dose needed for cure.

Certain plant compounds alter the pharmacological actions of others, change their physicochemical properties, influencing biochemical parameters such as solubility, bioavailabilty, and activity. Some compounds enhance immune responses while others attack microbial organisms, weakening them and making them more susceptible to the heightened immune system. And still others specifically work to reduce viral and bacterial defenses to antimicrobial plant constituents so that the plant's antibacterial and antiviral compounds are more effective.

Plants suffer bacterial and viral infection, just like we do. One of the things they do to deal with bacterial infections is produce antibacterial substances such as berberine in order to deal with them. Correspondingly, all bacteria, to differing degrees, have learned to deal with antimicrobial substances, most simply, to protect themselves from antimicrobial attack. One way they do this is to utilize
multidrug-resistance pumps. MDRs act to pump antibacterial substances that get into a bacterial cell out again. In response, plants, over time, innovated chemical constituents that would deactivate MDRs.

Berberis fremontii
(also known as
Mahonia fremontii
), one of the berberine-containing plants, for example, contains a compound, 5′-methoxyhydnocarpin (5′MHC), that is a potent MDR inhibitor of the efflux pump found in some Gram-positive bacteria, especially staphylococci. The plant then, when used medicinally, acts synergistically. One compound, 5′MHC, inactivates the MDR in the staph organisms, and another, berberine, kills the bacteria. (And yet another compound in the plant, porphyrin pheophorbide A, acts synergistically with both of them to kill MRSA organisms.) Sublethal doses of berberine, in numerous experiments, when combined with 5′MHC, become decidedly lethal. The compound 5′MHC itself has no antibacterial activity at all. Not surprisingly 5′MHC is common among the berberine-containing plants.

Because of the nature of this book, I am going to primarily explore plants that contain potent efflux inhibitors that deactivate those particular bacterial resistance mechanisms and, as well, plants that allow more effective penetration of plant compounds into the body. The field is still new; there isn't a lot to work with yet, but I hope that this chapter will give you a good idea of the complexity that is possible when looking at synergists. I hope it will stimulate you to deepen the work yourself, for all of us are going to need to know these things.

Something to keep in mind: herbalism is and always will remain an art. Analytical knowledge, while important, has to be combined with a
feeling
for the craft, for the plants, for the people who come to us for help, and … for the bacterial organisms themselves. From this comes art … and the ability to truly reason while at the same time developing a genuine capacity to heal.

As I've said before, we need both feeling
and
thinking for this craft to flourish inside us, and behind it all, a deep and abiding love for the plants and the earth from which they, and we, come.

To begin I'll just look briefly at a few of the synergists that have promise for the future, then I will get into several in more depth and explore how to use them for the treatment of resistant bacterial infections.

Most of the current synergy research taking place is looking at plants and plant compounds that can reverse drug resistance. Unfortunately, for my purposes anyway, most of the resistance-modifying studies that have taken place are looking at reducing the resistance of various forms of cancer to pharmaceuticals. I am not covering those here but am focusing solely on those that have been found to modify resistance in bacteria. MRSA is the bacteria upon which most study of medicinal plants' ability to modify resistance has occurred.

In the list that follows, most of the plants were tested by using an antibiotic on a resistant organism, then adding the plant to the mix and seeing what happened. Once the herb, or its constituent(s), were combined with the antibiotic, the antibiotic either became effective or was so at much reduced levels, usually by a factor of four to eight, though in the case of thyme, the effectiveness threshold of tetracycline against MRSA went from 4 to 0.12 mg/L. Further tests were then conducted to find out just which bacterial efflux pumps were inactivated by the plant.

Dalea versicolor
and
Dalea spinosa
both contain substances that are mildly antibacterial but others that specifically inhibit a particular efflux pump (NorA) in multidrug-resistant
Staphylococcus aureus.
They also inhibit the Bmr efflux pump found in
Bacillus subtilis
.

Ipomoea murucoides
, Mexican morning glory, contains a number of compounds that are also potent inhibitors of the NorA efflux pump
in resistant staph. These are, to date, the most potent inhibitors of NorA found, increasing the effectiveness of antibiotics 16-fold.

Geranium caespitosum
also has a potent efflux inhibitor active against MRSA. It potentiates the activity of the plant antimicrobials berberine and rhein as well as the antibiotics ciprofloxacin and norfloxacin. Other geraniums act similarly; these plants are exceptionally good to combine with berberine in the treatment of GI tract infections such as
E. coli
and cholera.

Cymbopogon citratus
, lemongrass, while having only mild antibacterial activity itself, is an exceptionally potent synergistic activator of antibiotics against MRSA.

Rauwolfia serpentina
and
R. vomitoria
are active against the Bmr efflux pump in
Bacillus subtilis
, the NorA and Tet(K) pumps in MRSA, the PmrA pump in
Streptococcus pneumoniae
, and an ABC transporter that is associated with ciprofloxacin resistance.

Epicatechin gallate
and
epigallocatechin gallate
, both in green tea (
Camellia sinensis
), have been found to be highly potent efflux inhibitors for both MRSA and
Staphylococcus epidermidis
. They inhibit both NorA and Tet(K) efflux pumps.

Rosmarinus officinalis
(rosemary),
Thymus vulgaris
(thyme), and
Lycopus europaeus
(gypsywort, bugleweed) have been found effective against the Tet(K) efflux pump in
E. coli
and MRSA and the Msr(A) pump in MRSA.

Prosopis juliflora
(and other
Prosopis
species—the mesquites), a very good medicinal tree and intense invasive, contains a number of potent piperidine alkaloids, one of which has been found to be a very potent inhibitor of the NorA pump in MRSA.

Extracts of myrrh gum (
Commiphora
), gotu kola (
Centella asiatica
), wild carrot (
Daucus
), licorice, and bitter orange (
Citrus aurantium
) are all effective in inhibiting the AcrAB-TolC efflux transporter that is present in a number of Gram-negative bacteria. (They are especially effective against multidrug-resistant
Salmonella enterica
var.
typhimurium.
) This efflux mechanism is a homologue of the MexAB-OprM efflux transporter that is widely present in resistant
Gram-negative organisms. Both pumps affect a wide range of antibacterials. When used with pharmaceuticals, these plants reduced the MIC (minimum inhibiting concentration) by factors of 4 to 32.

Thymus vulgaris
, thyme, inhibits the MexAB-OprM efflux pump and its gene expression. MexAB-OprM is heavily involved in the removal of tetracycline, beta-lactams, fluoroquinolones, chloramphenicol, novobiocin, macrolides, ethidium bromide, aromatic hydrocarbons, and homoserine lactones. Thyme essential oil, in tiny doses, one or two drops, when taken directly by mouth will enter the bloodstream immediately. If combined with herbs such as cryptolepis, it will potentiate their action against Gram-negative bacteria. Remember:
Tiny
doses.

The problem with most of these plants (gotu kola and licorice are exceptions) is that they are not highly systemic; that is, they are only moderately, if at all, present in any quantity in the blood. This makes their use as systemic synergists difficult—though of course they can be used topically and directly in the GI tract.

The next two are
most likely
systemic, though I don't know them well enough to say, and the final one
is
systemic and could be used to a limited extent as a systemic synergist for some resistant bacteria.

Caesalpinia benthamiana
(syn.
Mezoneuron benthamianum
) and
Securinega virosa
are two fairly important but relatively unknown (to Western herbalists) medicinal plants. The first has a wide activity against both Gram-negative and Gram-positive bacteria and is used to treat dysenteric diseases, and early indications are it may be systemic in nature. The second plant has some similar actions, especially in its wide use for dysenteric diseases. Both are efflux inhibitors. They definitely warrant further study.

Punica granatum
(pomegranate), the final plant in this list, is synergistic with ampicillin, chloramphenicol, gentamicin, tetracycline, and oxacillin against 30 different MRSA and MSSA (methicillin-sensitive
Staphylococcous aureus
) strains. The plant extracts inhibit ethidium bromide efflux mechanisms in a number of different types of
bacteria. There is also some evidence, not conclusive, that it is effective against the MexAB-OprM efflux pump in Gram-negative bacteria.

Pomegranate is systemic in that many of its constituents are circulated widely in the blood (peak in 1 hour, lasting about 4 hours), but how effective it would be to use it in practice, I don't know. The plant has not been considered to be a synergist in any culture that uses it and really not much as an antibacterial in any of the healing systems I have looked at. It has been used for millennia in Ayurveda but primarily as an astringent (juice) somewhat like cranberry juice, or for intestinal worms (bark/root).

However, recent research is showing some interesting activity in the plant in the treatment of high blood pressure, the prevention of normal cellular degeneration that accompanies aging, reducing DNA damage, and reducing stress levels in the body.

I will now explore three synergistic plants in detail: licorice, ginger, and black pepper and its primary constituent, piperine.

Family:
Leguminosae

Species Used:
There are 18 or 20 or 30 species in the genus
Glycyrrhiza
(this gets tiresome—make up your minds). They are native to Europe, North Africa, Asia, Australia, and North and South America. All species have been used medicinally, but the two most common are
Glycyrrhiza glabra
(the European licorice) and
Glycyrrhiza uralensis
(the Chinese). Russian licorice,
G. echinata
, is often used in that region; the American licorice
G. lepidota
is rarely used these days in spite of its wide native range but was frequently used as a medicinal by the indigenous peoples in the Americas. (And, yeah, they used it just the same way.)