Studies by scientists at Emory University suggest that traditional plant-based remedies used during the American Civil War to treat soldiers’ wounds could represent a source of modern-day antibiotics for some of the most dangerous multidrug-resistant bacteria that are associated with serious wound infections.

Conventional medicines were scarce during the 1861–1865 war, and the Confederate Surgeon General commissioned a guide on medicinal plants that were native to the southern U.S. states, and which were used in traditional Native American medicine. The Emory University-led team’s tests on extracts from three of the plants in the guide has confirmed their antiseptic properties and showed that they prevent growth of one or more of the multidrug-resistant bacteria: Acinetobacter baumannii, Staphylococcus aureus, and Klebsiella pneumonia.

“Our findings suggest that the use of these topical therapies may have saved some limbs, and maybe even lives, during the Civil War,” said ethnobotanist Cassandra Quave, PhD, assistant professor at Emory’s Center for the Study of Human Health and the School of Medicine’s department of dermatology. “Ethnobotany is essentially the science of survival—how people get by when limited to what’s available in their immediate environment,” she added. “The Civil War guide to plant remedies is a great example of that.” Quave is senior author of the researchers’ paper, which is published today in Scientific Reports and titled, “American Civil War plant medicines inhibit growth biofilm formation, and quorum sensing by multidrug-resistant bacteria.”

Antibiotic resistance is a growing global public health threat. Bacteria are very good at evolving, and so a rise in antibiotic resistance is “an inevitable response to antibiotic use,” the authors wrote. “Any single antibiotic, then, is not a permanent solution but another step in the struggle against infection.”

Modern antibiotics weren’t available during the American Civil War, and there was also no concept of germ theory. Formal physician training was rudimentary, and an antiseptic was defined simply as “a tonic useful to prevent external or internal mortification.” Onions, for example, were used to treat powder burns, but only now do scientists know that onions and garlic contain antimicrobial agents that impact on two features of bacterial pathogenicity, quorum sensing and biofilm formation.

Biofilms comprise communities of bacteria and extracellular mixtures of polysaccharides and proteins that can physically protect the microorganisms from antibiotics, the researchers explained. Biofilms can attach to surfaces, and are a particular problem on medical implants. Quorum sensing is a form of bacterial cell-cell communication system through which the organisms may secrete chemical signals and toxins, or display other pathogenic activity, which is triggered in response to population density.

Although inhibiting quorum sensing and biofilm formation may not directly kill the bacteria, these approaches can still have therapeutic value, the researchers stated. “In the absence of new antibiotics, multidrug-resistant infections may be treatable by administering biofilm inhibitors or quorum quenchers to increase the vulnerability of bacteria to the immune system or conventional antibiotics.” As Quave commented, “There are many more ways to help cure infections, and we need to focus on them in the era of drug-resistant bacteria.”

During the latter half of the American Civil War, a Union blockade prevented the Confederates from importing conventional medicines such as quinine, which was used to treat malaria, and morphine and chloroform, which were used to treat pain. Botanist Frances Porcher was commissioned by the Confederate Surgeon General Samuel Moore to find and catalog regionally native medicinal plants that could be used as alternatives to these usual drugs. His book, titled “Resources of the Southern Fields and Forests, was published in 1863 and included 37 plant species that were used as antiseptics to treat gangrene and other infections.

Moore then used Porcher’s book as the basis for a field guide of native plant medicines, which could be used by army physicians to treat soldiers. At the time amputation was frequently carried out to treat wound infections, and it’s estimated that about one in 13 surviving Civil War soldiers had at least one limb amputated. “I was surprised to learn that far more Civil War soldiers died from disease than in battle,” commented Micah Dettweiler, PhD, who is first author of the paper in Scientific Reports. “I was also surprised at how common amputation was as a medical treatment for an infected wound.”

“Our research might one day benefit modern wound care, if we can identify which compounds are responsible for the antimicrobial activity,” said Emory researcher Micah Dettweiler, shown with a stalk of the shrub known as the devil’s walking stick (Aralia spinosa). [Stephen Nowland, Emory University]
The resulting medicinal plant field guide, titled, “Standard supply table of the indigenous remedies for field service and the sick in general hospitals,” even included methods of collecting, preparing and administering the plant extracts. For their research, the Emory University-led team focused on investigating three of the guide’s plants that were available on the Emory campus. These were the white oak (Quercus alba) and the tulip poplar (Liriodendron tulipifera)—both trees—and a woody shrub known as the devil’s walking stick (Arala spinosa). Specimens of each plant were gathered according to Porcher’s specifications, and included extracts from the white oak bark and galls, the tulip poplar leaves, root inner bark and branch bark, and the devil’s walking stick leaves. The extracts were then prepared tested on the three multidrug-resistant bacteria that are associated with wounds.

Aceinetobacter baumannii is also known as “Iraqibacter” because of its association with wounded combat troops returning from the Iraq War. The organism is resistant to most first-line antibiotics. “It’s emerging as a major threat for soldiers recovering from battle wounds and for hospitals in general,” Quave said. Staphylococcus aureus is possibly the most dangerous of many common staphylococcus bacteria, and can spread from skin infections or medical devices to infect other organs. Klebsiella pneumoniae is a major cause of hospital infections and can result in potentially deadly pneumonia and septic shock.

White oak leaves and marble-sized galls. Galls are growths on plants caused by invasions of parasites, viruses, fungi and bacteria—making galls centers of activity for both attacks on a plant’s system and a plant’s defense of those attacks. [Stephen Nowland, Emory University]
Laboratory tests on the three medicinal plants showed that extracts from the white oak and tulip poplar blocked growth of S. aureus, and the white oak extracts also inhibited A. baumannii and K. pneumonia growth. Extracts from both of the plants also blocked S. aureus biofilm formation. The devil’s walking stick extracts inhibited both biofilm formation and quorum sensing in S. aureus, which essentially “disarms” the bacteria.

“Extracts of L. tulipifera, A. spinosa, and Q. alba displayed inhibitory activity against bacteria that cause skin and soft tissue infections, substantiating their use as antiseptics during the American Civil War,” the authors concluded. “It may be hoped that Porcher’s work with medicinal plants saved many lives and limbs … These medicinal plants may be useful in modern medicine as treatments for antibiotic-resistant bacteria.”

In fact about 25% of modern drugs are derived from natural products used in traditional medicine, the authors stated. “Natural products—compounds produced by living organisms—are used directly as medicine by an estimated four billion people for whom traditional medicine is a primary healthcare resource.” And one of the potential benefits of natural product extracts is that they contain potentially dozens or even thousands of compounds, and so can exhibit multiple mechanisms of action.

“In vivo testing of the antibacterial properties of extracts active in vitro is also a logical next step in this research,” the investigators suggested. “Given the potential of some of these extracts as adjuvants rather than direct antibiotics, they may be tested as adjuvants with existing, FDA-approved antibiotics for the potentiation of antibacterial activity in wound infections.”

“Our research might one day benefit modern wound care, if we can identify which compounds are responsible for the antimicrobial activity,” Dettweiler suggested. Finding which compounds in the extracts exert antimicrobial effects will then allow the next stage of in vitro testing, according to co-author Daniel Zurawski, PhD, chief of pathogenesis and virulence for the wound infections department at the Walter Reed Army Institute of Research. “ … it is my hope that we can then [further] test these molecules in our world-renowned models of bacterial infection.”

The researchers commented that it may be useful to test other plants in Porcher’s work for therapeutic potential. “ … given the activity seen in the extracts tested in this study, it may be worthwhile to investigate the antibacterial properties of other plants recorded as antiseptics in Porcher’s book. In total, 37 plant species were described as having antiseptic applications. As the global spread of antibiotic-resistant strains of bacteria continues, it is increasingly important to consider all possible sources of new, and perhaps old, treatments.”

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