# History as a Source of Innovation in Antimicrobial Drug Discovery

Basma Abdallah, Hassan Ait Benhassou, Laila Sbabou, Régine Janel-Bintz, Laurence Choulier, Véronique Pitchon, Pierre Fechter

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Basma Abdallah, Hassan Ait Benhassou, Laila Sbabou, Régine Janel-Bintz, Laurence Choulier, et al. History as a Source of Innovation in Antimicrobial Drug Discovery. Biomedical and Pharmacology Journal, 2023, 16 (2), pp.739-752. 10.13005/bpj/2656 . hal-04237679

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History as a Source of Innovation in Antimicrobial Drug Discovery

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Basma Abdallah<sup>1,2,3,4*</sup>, Hassan Ait Benhassou<sup>1</sup>, Laila Sbabou<sup>2</sup>, Régine Janel-Bintz<sup>4</sup>,

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Laurence Choulier<sup>3</sup>, Véronique Pitchon<sup>5</sup>, Pierre Fechter<sup>4*</sup>

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<sup>1</sup>Prevention & therapeutics center, Moroccan Foundation for Science, Innovation &

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Research (MAScIR), Rabat, Morocco.

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<sup>2</sup>Laboratory of Microbiology and Molecular Biology, University Mohamed V Rabat,

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Faculty of Sciences, Rabat, Morocco

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<sup>3</sup>CNRS, UMR 7021, Laboratoire de Bioimagerie et Pathologies, Faculté de Pharmacie,

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Université de Strasbourg, 67401 Illkirch, France

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<sup>4</sup>CNRS, UMR 7242, Biotechnologie et Signalisation Cellulaire, Institut de Recherche

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de l'Ecole de Biotechnologie de Strasbourg, Université de Strasbourg, 67400 Illkirch-

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Graffenstaden, France

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<sup>5</sup>CNRS, UMR7044, Archéologie et Histoire Ancienne : Méditerranée- Europe, MISHA,

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Université de Strasbourg, Strasbourg, France

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*Corresponding author: P. Fechter - +33 (0)368854820 - p.fechter@unistra.fr

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Running title: from past to present in antibiotic research

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24 ORCID of all authors

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27 Basma Abdallah 0000-0003-4230-3512

28 Hassan Ait Benhassou 0000-0002-5815-3531

29 Laila Sbabou 0000-0002-0948-4553

30 Régine Janel-Bintz 0000-0002-6682-8551

31 Laurence Choulier 0000-0003-1493-9775

32 Véronique Pitchon 0000-0003-3657-2724

33 Pierre Fechter 0000-0001-5912-361X

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**Abstract**

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The proliferation and prevalence of antibiotic-resistant bacteria despite modern medicine is considered as one of the most alarming threats to global health. In the fear that the antibiotics that work today may not work tomorrow, there is an urgent need to search and develop newer drugs or therapeutic strategies to fight against micro-organisms immune to our current approaches. From time immemorial, people have sought solutions to combat infections and have proposed countless remedies, traces of which can be found in manuscripts preserved over the past centuries. The re-examination and exploitation of these ancient remedies might be a key to a vast pool of potential therapeutic strategies or drug candidates against antibiotic-resistant pathogens. This, however, would first require the consideration of these ancient solutions as scientifically pertinent leads for new therapies. The aim of this review is to give, through a few examples, arguments in favor of rationality in the scientific approach of these past physicians as well as of a medicinal interest in studying these ancient pharmacopoeias. To narrow the scope of our research, we focused on the Arab Medieval Golden Medical Age, which went on to inspire occidental medicine hundreds of years after its preeminence. We further highlight the possibility of integrating these knowledge into innovative, modern therapeutic options.

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Keywords: *Arab Medieval Pharmacopeia*, *natural remedies*, *pathogens*, *antibiotic resistance*

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**Introduction**

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Pharmacy is born with humans, who found ways to relieve their physical suffering through remedies prepared with natural ingredient. Thanks to the synergy of the gift of writing and man's desire to alleviate his ailments, ancient and medieval pharmacopoeias contain information on the use of medical material, that may be from plant, mineral, or animal origin.

It is thus still possible that these thousand-year-old pharmacopoeias hold secrets that could contribute to nowadays medicines. Many leading drugs (anti-cancer, anti-malarial, painkillers, etc.) are indeed derived from these ancestral traditional pharmacopoeias [1]. However, of the > 30,000 plants with therapeutic virtues described in traditional pharmacopoeias, less than 5,000 have been studied [2]. The question is whether and how to exploit this vast pool of potential therapeutics [3,4].

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In the last decade, medicinal plant research has turned to old medicinal-botanical texts, to study the history and evolution of pharmacopoeias, and to identify lead compounds for new drug discovery [5-8]. Despite this pivot in research focus, experiments that test the activities of entire historical remedies are rare, difficult to conduct, and the subject of much misunderstanding.

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This is due to several factors including:

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- The folkloric image associated with ancient medicines. The frequent intrusion of the magical and the sacred hinders the objective evaluation of remedies while their development remained rationally designed at its base. It may therefore seem difficult to evaluate the biological effect of each of the ingredients. However, very often this interference is not constitutive, but superadded: the rational/irrational association can usually be clearly separated.

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Further, the diagnosis of a malady can also be complex, often involving supernatural aetiologies alongside natural causes. In contrast to modern medicine, which seeks a direct cause for a pathology, ancient systems often seek to flush out deep-seated causes. This disorganizes and devalues the care provided, which is nevertheless often rational.
81 - The difficulty of transposing ancient practices into our present culture. This requires
82 a huge interdisciplinary research effort alongside, a dialogue between disciplines, the
83 promotion of which is not yet obvious, a problem very well explained by Harrisson and
84 Connelly [9]. Furthermore, on the opposite of current medicines containing a single active
85 ingredient, medieval remedies are usually preparations made from several ingredients, acting
86 synergistically [10–12]. It is thus possible that each ingredient taken individually does not
87 carry a strong activity, but that the combination can bring a certain, desired effectiveness.
88 While this approach is not without interest, the effectiveness of the remedy, which is the sum
89 of its multiple actions, will be more difficult to evaluate and to determine, and is not
90 necessarily favored by current research.

91 - The juxtaposition of two medicines, traditional and modern. While modern medicine
92 has grown in power and prestige, traditional medicine fallen victim of trivialization and/
93 increasingly untrained body of people practicing this form of medicine over the course of many
94 years. This has resulted in some degradation of knowledge, and a more superficial scientific
95 approach. It is thus necessary to restore confidence and rationality in the study of traditional
96 medicines, and to find room for dialogue between both approaches, that are ultimately rather
97 complementary than opposed, i.e. [13–17].

98 Although discredited in recent years, traditional medicines have nevertheless been marked
99 throughout their history by a rationality, a scientific approach enabling the emergence of
100 remedies that we could quite rightly consider as innovative by modern standards despite being
101 designed millennia ago. It is important to remember that traditional practices were characterized
102 by the seal of research, carried out by prominent scientists who led to major discoveries and
103 developments. Ancient pharmacopoeias could again be considered as a relevant starting point
104 for the search for new remedies. This will be illustrated through a few examples from the
105 literature. We focused on the medieval Arab period perceived as the golden age of ancient
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medicine, and through the lens of the fight against microbial infections, one of the major
medical concerns of the medieval period.

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# 1. Antibiotic resistance

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Infections have marked human history. Even if nowadays, except for the COVID-19 pandemic, infections are considered less anxiety-provoking compared to other pathologies such as cancer, this has not always been the case: at medieval times, drinking water, cutting, or injuring oneself could lead to dangerous or even fatal infections. As these infections were a daily preoccupation, physicians also developed many leading remedies to counter them [4].

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The advent of antibiotics, with Fleming's discovery of penicillin in 1928, a compound produced by the fungus *Penicillium notatum*, revolutionized the treatment of infections [18,19], leading to the belief that microbial infections were 'over'. The use of traditional medicines was thus no longer relevant and lost much of its prestige. This was nevertheless regardless of the ability of bacteria to resist antibiotics. If microbes can produce antibiotics (most of the antibiotics used are of microbial origin), it is indeed logical that other microbes have found ways to resist these same antibiotics. These resistances have then spread widely with the unreasonable use of antibiotics, i.e. [20–22].

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Indeed, quite quickly after their introduction to the market, bacteria strains resistant to antibiotics were detected. This was the case for penicillin, with resistant *Staphylococcus aureus* found in the 1940s [23,24]. *Streptococcus pyogenes* resistant to sulfonamide was also readily detected in military hospitals during the second World War [25–27]. *Mycobacterium tuberculosis* with streptomycin resistance was revealed as well in 1948 [28]. Resistance to multiple drugs was first observed in the late 1950s to 1960s among enteric bacteria, like *Escherichia coli*, or other from the *Shigella* and *Salmonella* genus [29]. These resistances cause

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also a gradual re-emergence of pathologies like tuberculosis, since the 1980s, mainly due to multi-drug resistant strains, enhanced by emergence of the human immunodeficiency virus [30].

As a consequence of the pervasiveness of the above strains of bacteria, the emergence of antibiotic resistance has been rising rapidly all over the world. Ultimately, a new resistance appeared with every new antibiotic synthesized (Figure 1). Subsequently, we are now presented with an ever-increasing global health threat. In 2019, a study showed the involvement of antibiotic-resistant bacteria in the deaths of greater than 1.2 million people [31]. This may be attributed to different factors, such as the abusive use of antibiotics, as well as a shortage of new drug development by the pharmaceutical industry [32].

In the fear that antibiotics that are effective today might no longer be functional tomorrow, and with the rapid spread of antibiotic resistance, there is an important need to develop new strategies to limit the use antibiotics and to find new therapeutic solutions. Ancient societies have used and/or combined countless natural substances to treat diseases, trying, testing, and improving these strategies over the course of many centuries. Keeping these facts in mind, it seems only logical that they could very well serve as the basis for the discovery of new therapeutic strategies. However, the establishment of interdisciplinary consortia dedicated to the study of these remedies must be implemented, as well as the demonstration of the interest, feasibility, and future prospects of such approaches.

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## 2. Rationality in the design of remedies

If different pinpoint studies already highlighted some interest in studying past remedies or highlighted antibiotic use from past records, i.e. [33–40], the consideration of these past remedies as a reservoir of pertinent strategies to combat infection would require a more

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complex and coordinated strategies, involving intense collaboration between art, social and
experimental sciences.

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A pioneering interdisciplinary consortium (Ancientbiotic, https://ancientbiotics.co.uk/) has been set up to study a 10th Century medical text known as ‘Bald’s Leechbook’ containing a plentitude of remedies. From this book, a collyrae (Table 1) has been chosen to highlight the potential of these medicines to combat infections. The goal was equally to study the medical approaches of past physicians as much as to demonstrate the efficacy of an ancient remedy. By faithfully reproducing this remedy, the authors were able to show that it drastically limited the growth of bacterial pathogens like *Staphylococcus aureus*, *Pseudomonas aeruginosa* or *Neisseria gonorrhoeae* in vitro, and/or on a mouse model of eye infection, with a reasonable safety profile [41–44].

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The same studies also showed that the mixture of ingredients in Bald's eye drops is more effective than the addition of each individual components, implying that the combination of specific ingredients, none of which may have significant antibacterial activity, the mixture overall may still present promise. Consequently, it seems possible that some of the combinations developed by these physicians were designed through rational methods. Furthermore, this permits the plausibility that one could construct a remedy of therapeutic potential with individually uninteresting ingredients. So, the idea would be to consider these ingredients in the context of all or part of the remedies, rather than investigating each ingredient individually.

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As a follow-up of this study, the consortium also developed a software to analyze the entire manuscript on order to highlight the most promising remedies. Groups of ingredients were revealed. Some of them were often used together, such as aloe vera and sarcocolla [45]. Another recent computer analysis equally highlighted the recurring appearances of combinations of ingredients, like saffron and opium or fennel and celery seeds, when analyzing remedies for

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179 urinary tract diseases identified in different Arabic pharmacopoeias spanning over the course
180 of > 3 centuries [46]. These re-occuring combinations point to a rational approach to the
181 development of treatments, where a base of certain ingredients would have been maintained
182 and used as a framework for the design of new candidates. The same ingredients could produce
183 synergistic activity if combined, and should deserve special attention. Thanks to these studies,
184 it becomes more and more evident that the science of medicine in medieval times was the result
185 of a very rational and scientific approach, far from the folkloric image it usually has. Further
186 study of remedies from other manuscripts and ancient practices will be required to confirm
187 these initial hypotheses and/or to possibly allow the identification of innovative active
188 principles from complex combinations or even unexpected materials [35,47], for example
189 through the development of other consortia.

190 While traditional remedies were developed from such common ingredients, many remedies also
191 contain toxic molecules, among which the most emblematic being heavy metals, such as lead,
192 mercury, and arsenic. Reconsidering these remedies for future development also requires to
193 prove that ancient physicians perfectly mastered the use of these ingredients, took into account
194 their toxicities, and did not take ill-considered risks concerning the health of their patients. One
195 example is lead, widely used since antiquity to prepare make-up products (including kohl) or
196 remedies. Two recent studies have analyzed such uses, based on makeup found in Egyptian
197 tombs [48], and the reconstitution of a cutaneous remedy reported by Al Kindi (Table 1), from
198 the medieval Arab period [49]. These two studies demonstrated that ancient alchemists
199 mastered the transformation of metals and were able to confer them different therapeutic
200 potentials, depending on the transformation processes used. In the “khols” used for make-up,
201 litharge was transformed into laurionite and phosgenite, with pro-inflammatory properties,
202 which prevented infections [48]. Reconstruction and analysis of the ancient remedy showed
203 that alchemists were also able to obtain soluble lead with anti-inflammatory properties, to
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promote healing [49]. Moreover, the toxicity of lead was reported as early as antiquity [50]. As an anti-infective, it was mostly used cutaenously. Such use limited the diffusion of this metal in the body, restricting it action on the local site of infection. These precautions may therefore have changed the benefit-risk balance of lead. Overall, the evidence suggests that ancient physicians knew about the inherent toxicity of toxic ingredients like metals, and handled carefully their use.

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These few exemples show us that the study of the history of medicine combined with more modern investigation to characterize these remedies could prove the rationality of the approaches followed by these physicians. One of the periods where this scientific approach was at its peak, both in terms of the variety of actors and of the scientific approach, is the medieval Arab period (Table 1). The methodology applied by these scientists could still be relevant today and will be explained in the following section.

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### 3. The Arab medieval Golden age of medicine

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Among the scientific fields studied in the medieval Arab world, medicine was certainly the most studied and the most developed. It is customary to say that this was the golden age of Arab medicine with considerable scientific contributions between the 9th and 13th centuries, i.e. [51–55]. Many of the achievements of Arab-Muslim physicians were based on the legacy of Greek and Roman physicians [51,56]. This effervescence of knowledge and intelligence then spread throughout the world and profoundly influenced medical theory, surgical practice and other disciplines.

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Several factors have led to this Golden Age among them being religious support. As this period was deeply religious, such positions could easily favor, delay, or condemn medical progresses.

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The guidelines of the Prophet clearly for example encouraged such studies. The extension of the Muslim Empire during this time brought out an exchange of ideas from various part of the world from India to Iran, or Spain, (Figure 2). Communication routes also became safer, facilitating travel and trade. Alongside these developments, Arabic language was unified as an international one, which facilitated the exchange of scholarly ideas [54]. The ancient manuscripts of greek, latin or even sanskit [57] were translated in Arabic by the most competent scholars. Another significantly contribution to the Golden Age was the establishment of a paper mills in Baghdad (for a long time the nerve center of the Arab-Muslim world [58]) to replace parchment (skin of animals) or papyrus (plant origin) by paper using linen. This enabled many people to gain access to books and develop their education [54]. The most precious texts were stored in the House of Wisdom, founded in Baghdad in 1005 by the Caliph Al Mamun [56].

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Important advances were also made in chemistry, where Arab alchemists became familiarized with plants and developed different techniques such as distillation, crystallization, calcination, etc [54]. An entire outgrowth of alchemy consisted in isolating and studying a broad variety of natural sources, minerals, and compounds, to discover a magic 'elixir' or a medical potion that would preserve people from all fatal diseases.

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Likewise, in microbiology, plague and leprosy were considered as infective and contagious diseases. For example, Islamic practitioners introduced the concept of quarantining (XIth century) as a form of disease control. Hygienic methods were also implemented at the same time, in the form of proper sterilization, putting in place practices such as the use of alcohol prior to surgery and skin wounds treatment [54].

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253 Developments also occurred in pharmacology. Practitioners became acquainted with herbs,
254 introduced new drugs such as camphor, musk, sandalwood, developed excipients, created
255 flavoring extracts, and experimented with poisons and antidote [59,60]. The first pharmacy was
256 established in Baghdad in 754. Four centuries later, the pharmacology science was separated
257 from both medicine and alchemy, these disciplines becoming independent (illustrated Figure
258 3).

259 *Medical education and institution*

260 Physicians during this era had to follow long training courses, often being six to seven years in
duration. This education comprised of an initial theoretical training in sciences, subsequently
261 followed by clinical training in hospitals. Medical practice was even governed by a code of
262 ethics towards patients, colleagues, and community [61,62].

264 Secular hospitals developed throughout the Arab world, the first being established in Damascus
265 in 706. These hospitals were well equipped. Patients monitoring, drug development and clinical
266 trials were reported and provided key record for the development of the scientific method [63].

267 *Famous figures of the Arab medicine age*

268 Among the era's many prominent figures was Zakarya Al-Razi, known in Latin as Rhazes
269 (Figure 2, Table 1), a pharmacologist and physician from Persian origin who headed the hospital
270 founded in Baghdad [64]. Zakarya Al-Razi chose to devote his life to medical research and
271 became the founder of chemotherapy by using the mineral drugs for external and internal use
272 in cancers [64]. Since his youth, he was interested in alchemy, and years later he was the first
273 to introduce metal-chemical preparations such as arsenic, copper sulfate, iron sulfate, and
274 different forms of mercury to develop new drugs [65]. He went on to write his famous book *Al- Hawi*, an encyclopedia of 30 volumes that provides a general description of disorders, fevers,
275 plagues, and skin diseases, that was accompanied by a complete pharmacopeia, tables of
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terminology, weights, and measures [65]. It is noteworthy that he was the first to use opium as an anesthetic and that he tested it on animals before administrating it to humans [64].

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One of the most famous muslim scientist is Abdu Ali Ibn Husayn ibn Abdullah Ibn Sina, also known as Avicenna (Figure 2, Table 1). Of persian origin, from Rayy, he was known as the prince of medicine and he developed a methodological approach that would be taught in European universities until the 19th century [64]. His book *Al-Qanun fi al-Tibb -Canon of Medicine-* became a famous medical works, considered to represent the first pharmacopeia, including more than 600 medicinal chemical, and physical properties [66]. In addition to these accomplishments, Avicenna was the first to describe many different microbiological diseases such as anthrax and tuberculosis, and emphasized the crucial role of hygiene and dietetics [54]. He stressed the need to study new drugs before releasing them to the patients by setting rules to test their effectiveness [64].

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Another interesting figure in the history of medieval science is Abu Yusuf Yaaqub Ibn Ishaq Al Kindi (Figure 2, Table 1), considered as the Father of Arab philosophy. He was interested in a variety of subjects ranging from metaphysics, philosophy and logic to optics and pharmacology [67]. Among his many medical writings, the most reputable and well-known might well be the medical formulary “Aqrabadhin”. This term is derived from the Greek word for 'list'. The book details the pharmaceutical preparations derived from botanical sources, animals, and minerals, in the form of lists of medications [67,68]. He also wrote a treatise *Risala fi ma' rifat quwwat al-adwiya al-murakkaba*, translated as *De gradibus*, and devoted to quantify the strength of drugs by exploiting mathematical rules [69].

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Diya al-Din Abu Muhammad Abdallah Ibn Ahmad Ibn al Baytar (Figure 2, Table 1) is another famous Arab scientist, a famous Muslim botanist and pharmacologist during the Medieval times. He belonged to a scientific family. His father Ahmad Ibn Abd-al Malik taught him his knowledge and passion for natural sciences [70]. He studied the Galenic pharmacopeia, which

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302 was based on the identification of the active principles of medicinal plant extracts. His capital
303 work, entitled, *Kitab al-Gami' li-mufradat al-adwiya wa-l-agdiya* translate to 'Collection of
304 simple remedies and food' [69] is considered as his seminal work, based on Dioscorides, Galien,
305 Al-Razi and Ibn Sina, on which he applied his own observations and corrections and mentioned
306 the simple nutrients and about 1400 drugs based on plants, animals, and mineral reigns [70].

307 *Drug development during the Arab Medieval ages*

308 During the Medieval ages, Arabs contributed riveting interesting advances to health and
309 medicine. During this time, the use of drugs still relied upon scientific hypotheses introduced
310 by the Greeks, related to ‘the theory of bodily humors’. Essentially, this theory states that
311 humans fell ill due to imbalances of these humors in the body [71]. Hippocrates (Figure 2,
312 Table 1) stated that the human body is made up of four substances: yellow bile, black bile,
313 water, and blood, to which he connected an element in the universe with atmospheric conditions
314 for each substance. Arab physicians agreed with this theory [72] and affirmed that physical and
315 spiritual wellbeing is essential, and that a disease should be viewed as an opportunity to purify
316 and balance the emotional and physical feelings via rest, a regime of healthy food, breathing
317 fresh air, and practicing good hygiene [73]. Even if this theory has proven incorrect, the
318 development of drugs still responded to scientific standards, and were further framed by ethic
319 rules [74].

320 It is important to note that the origin of drug development has been based on the sum of
321 accumulated knowledge from pre-Islamic periods, such as that of the Egyptian or Chinese
322 medical systems, the Greek and Roman legacies still remaining the basis of the developed
323 knowledge throughout the Arab Medieval ages. Arab physicians then improved these
324 knowledge, enhancing also the concept of trials which is the basis of nowadays scientific
325 approaches. Once a remedy was identified, either based on plants, animals, metals and/or
326 minerals, its efficiency and toxicity was tested. Then, the administrated remedy could be either
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a simple diet or a simple drug based on plants, minerals and metals, or to a mixture of one or
more of the aforementioned (Figure 4) [74,75].

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Ibn Sina largely studied the nature and qualities of simple drugs in vol. 2 of the *Canon*, he then proceeded to set rules to be respected in the drug development process. These remained the basis of testing drugs [74]:

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- The drug must be cleaned from any foreign agents.

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- Drugs must be tested on two different diseases to be sure of the effects.

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- The mechanism of action must be monitored.

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- The drug must be tested on animals then on human, because if it is carried on animals only, the effect on humans cannot be proven.

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Altogether, it appears that Arab physicians developed a scientific method based on experimentation, evidence-based knowledge, clinical trials, animal and/or human trials, concepts that are also found in the contemporary scientific method.

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## Conclusions - Perspectives

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Health care systems have always been deeply embedded in economic, religious, and societal beliefs, and therefore are reflections of their perspective eras. Where aforementioned periods are religious, an inter-relationship between medicine and belief is widely found, in different forms depending on the period, disturbing the perception and relevance of the medical and pharmacological advances of these periods. However, these inter-relations have never prevented the rational development of medicine, and all the great civilizations have developed a wisdom, an art of health and healing that is, empirically solid with proofs of effectiveness. This rationality reaffirmed in past scientific developments encourages to re-investigate ancient

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practices and pharmacopoeias. The latest technological advances also allow to surmount the barriers of the study of these ancient remedies [76–78].

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The greatest benefit of history is the ability to collect knowledge from the past and integrate it with that of today to improve future knowledge. Since ancient times, plants, insects, animals, minerals, turned out to be an exceptional large source of bioactive molecules: they have already provided mankind with new first-class remedies [79]. The study of these pharmacopoeias is now turning to more complex remedies that provide a synergy of action compared to isolated ingredients. This synergy allows therapeutic strategies to be multiplied from ingredients which, taken individually, would have be of little medicinal interest. These studies are nevertheless complex and require the establishment of important interdisciplinary networks, ranging from history to biology, to chemistry and to pharmacology. Recognition of these networks and the valorization of their added value remain a challenge.

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The Arabic Golden Age were an important period in the evolution of ancient medicines and laid the foundations for a modern scientific approach. Their knowledge largely inspired Western medicine from the Middle Ages to the Renaissance. The numerous manuscripts found allowed to collect a large amount of information on medical practices and pharmacopoeias, and to follow these practices in time and space. By focusing mainly on remedies preserved over a wide geographical or temporal scale, the highest potential of being of interest may be selected.

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The search for antibacterial solutions is particularly well suited to this approach, as infections were a daily concern in the Middle Ages, and the solutions proposed are numerous: we thus have access to a vast repertoire of potential solutions. This research is even more relevant in view of the context of increasing bacterial resistance to antibiotics. The unreasonable use of antibiotics, both in human and animal health, as a preventive measure, for pathologies that do not require antibiotics has led to a situation where the search for alternatives becomes crucial. These ancient pharmacopoeias contain a vast array of information on both innovative molecules

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and synergistic strategies making it more difficult for resistance to appear, while potentially reducing the impact on the surrounding microbiota (bactericidal molecules taken individually being less deleterious). Thus, it appears that history holds a vast repertoire of remedies that might lead to medical innovation. Another option for these remedies, some of which have been preserved throughout history, still used today in the traditional Arab pharmacopoeia, and whose efficacy has been validated historically and through today's scientific prism, is that they could find a place in an integrated healthcare offer.

Medical systems are constantly evolving. The introduction of a new medical system occurs when the old one is challenged. This evolution often results in an interweaving of innovations and old practices, even if the integration of ancient practices is done with parsimony or defiance [80]. This has always been the case, and is still true today, a time when we are witnessing a crisis in health care related to inadequate delivery and adaptation to changing patient expectations. This crisis of confidence amplifies the growing demand for complementary and alternative medicines, which have their origins in ancient and/or traditional practices. This is reflected in the growing number of patients (over 70% according to the WHO) who are already turning to these practices. And, even if there is a complementarity between these two forms of wisdom, modern medicine being on one hand and traditional medicines on the other, it is their connection that seems to be problematic today. This complementarity, which stems from differences in the way health and pathology are defined, studied and perceived, could also be at the source of the difficulties in uniting them. As such, it is imperative to study the cultures and societies that have laid the foundations of past medicine [81]. Characterizing the scientific approach by which these medicine and pharmacopoeias have been developed, understanding how the different health systems have intertwined with each other over time would help to rationalize the debate, and ultimately, why not, lay the foundations for a modern conception of a common medicine?
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**Authors contribution**

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All authors contributed similarly, and PF acted as project supervisor

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**Conflict of interest**

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The authors declared no conflict of interest

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**Acknowledgments**

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We would like to thank Cody Bowens for critical reading of the manuscript.

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**Funding**

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This project was financially supported by the French Ministry of Europe and Foreign Affairs,

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Ministry of Higher Education, Research and Innovation and the French Institute of Rabat (PHC

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TOUBKAL 2019, Grant Number: 41520SE; PHC MAGHREB 2022 Grant No 47455NH; by

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the University of Strasbourg (projet Interdisciplinaire - Emergence) Grant Number

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CF/PN/CB/N°2017-974-3, and by the program METALLO-MIX of CNRS - Grant Number

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21887. B. Abdallah was financed by the Mascir Foundation (Rabat), and by the PHC

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TOUBKAL.

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607 **17**: 1217–1220.

608

609
610 **Figure Legends**

611

612 **Figure 1. A timeline of the evolution of antibiotic resistance.**

613

614 **Figure 2. Map of the Arab Empire in Medieval times.** The name of famous scientists cited
615 in the text, their time and place of birth are given.

616

617 **Figure 3. Illustration of a medicine preparation.** Folio from a dispersed manuscript of an
618 Arabic translation of the *Materia Medica* of Dioscorides [56,82]

619

620 **Figure 4. Drug development process during the Arab medieval age**, adapted from [74,83]

621

622
<table><caption>623 **Table 1.** Glossary of terms and names used in the review</caption><thead><tr><th>Family term</th><th>Name</th><th>Description</th></tr></thead><tbody><tr><td>Infection</td><td></td><td></td></tr><tr><td></td><td>Present definition</td><td>Development in a living being of micro-organisms that can cause injury by multiplying and possibly secreting toxins or spreading through the bloodstream</td></tr><tr><td></td><td>Past definition</td><td>Infections are described by the symptoms they cause. Their description should inform us on the nature of the infection with today standard's. This usually demands a broad-ranging, interdisciplinary approach, to study the manuscript, understand the description of the disease, symptoms, the curative ingredients and infer from these descriptions a plausible causing agents, that is not without difficulties [84–86].</td></tr><tr><td>Professionnals</td><td></td><td></td></tr><tr><td></td><td>Physician</td><td>A person able to practise medicine, from the diagnostic to the treatment (except surgery)</td></tr><tr><td></td><td>Alchemist</td><td>A person who practises alchemy, the medieval forerunner of chemistry, concerned with the transformation or transmutation of matter, through distillation, crystallisation...</td></tr></tbody></table>
<table><tr><td>Pharmacist</td><td>A person who can prepare and sell certain medicines by prescription only. They were aware of the importance of raw materials, botanic and the importance of the preparation protocol precision</td></tr><tr><td>scholar</td><td>A person who is highly educated or has an aptitude for study.</td></tr><tr><td>Time period</td><td></td></tr><tr><td>Antiquity</td><td>30<sup>th</sup> century BC - 5<sup>th</sup> century</td></tr><tr><td>Medieval time</td><td>5-15<sup>th</sup> century</td></tr><tr><td>Arab medical golden age</td><td>9-13<sup>th</sup> century</td></tr><tr><td>Famous figures</td><td></td></tr><tr><td>Hyppocrate</td><td>Born around 460 BC in Cos and died in 377 BC in Larissa, was a Greek physician of the Periclean century, but also a philosopher, traditionally considered as the father of medicine</td></tr><tr><td>Dioscorides</td><td>Born between 20-40 in Anazarbe and died around 90. He was a Greek physician, pharmacologist and botanist whose work was a major source of knowledge about remedies of a plant, animal or mineral nature during the 1,500 years. He is the author of the treatise 'De materia medica'.</td></tr><tr><td>Zakarya Al-Razi</td><td>Born in 865 in the town of Clay, died around 925 in Tehran was a Persian multidisciplinary scholar who</td></tr></table>
<table><tr><td></td><td></td><td>made important contributions to medicine, alchemy and philosophy</td></tr><tr><td>Abu Yusuf Yaaqub<br/>Ibn Ishaq Al Kindi</td><td>Born in 801 in the town of Koufan, died in 873in Bagdad. As an encyclopaedic mind, he sought to synthesise, organise and evaluate all the knowledge of his time (philosophy, mathematics, astronomy, physics, chemistry, technology...)</td></tr><tr><td>Abdu Ali Ibn<br/>Husayn Ibn<br/>Abdullah Ibn Sina</td><td>born in 980 in Ravi, died in 1037 in Hamadan, philosopher and physician, author of reference works in medicine and philosophy</td></tr><tr><td>Diya al-Din Abu<br/>Muhammad<br/>Abdallah Ibn<br/>Ahmad Ibn al<br/>Baytar</td><td>born around 1197 in the province of Malaga and died in 1248 in Damascus, an Arab-Andalusian physician, who published several works in which he brought together the pharmaceutical knowledge of his time</td></tr><tr><td><strong>Remedies</strong></td><td></td></tr><tr><td>collyrae from the<br/>Bald's Leechbook</td><td>Make an eyesalve against a wen: take equal amounts of an Allium species and garlic, take equal amounts of wine and oxgall, mix with the alliums, put in a brass vessel, let stand for nine nights, clarify well, put in a horn and at night apply to the eye with a feather [44]</td></tr></table>
<table><tr><td>Lead-based cutaneous remedy from Al Kindi.</td><td>1 part of quicklime (CaO) and 1 part of litharge (PbO) are passed through a clay. They are covered with wine vinegar. Olive oil is added and also sheep fat. It is boiled together and stirred with a rod until it is mixed and almost black. The heating is renewed until the viscosity is like thick honey [49]</td></tr></table>
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