b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 9 (2 0 1 8) 212–219 ht tp://www.bjmicrobiol.com.br/ Review Lactoferrin, chitosan and Melaleuca alternifolia—natural products that show promise in candidiasis treatment ∗ Lorena de Oliveira Felipe , Willer Ferreira da Silva Júnior, Katialaine Corrêa de Araújo, Daniela Leite Fabrino Universidade Federal de São João del-Rei/Campus Alto Paraopeba, Minas Gerais, MG, Brazil a r t i c l e i n f o a b s t r a c t Article history: The evolution of microorganisms resistant to many medicines has become a major chal- Received 18 August 2016 lenge for the scientific community around the world. Motivated by the gravity of such a Accepted 26 May 2017 situation, the World Health Organization released a report in 2014 with the aim of providing Available online 11 November 2017 updated information on this critical scenario. Among the most worrying microorganisms, Associate Editor: Luis Henrique species from the genus Candida have exhibited a high rate of resistance to antifungal drugs. Guimarães Therefore, the objective of this review is to show that the use of natural products (extracts or isolated biomolecules), along with conventional antifungal therapy, can be a very promising Keywords: strategy to overcome microbial multiresistance. Some promising alternatives are essential Candida oils of Melaleuca alternifolia (mainly composed of terpinen-4-ol, a type of monoterpene), lacto- Lactoferrin ferrin (a peptide isolated from milk) and chitosan (a copolymer from chitin). Such products Melaleuca alternifolia have great potential to increase antifungal therapy efficacy, mitigate side effects and provide Chitosan a wide range of action in antifungal therapy. Natural products © 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). However, four species cause 96% of the infections: Candida Introduction albicans is the main etiologic agent, responsible for 42.5% of infections, followed by Candida tropicalis (27.3%), Candida para- Fungal infections are responsible for many deaths around the 3 psilosis (21.9%) and Candida glabrata (4.4%). world, in addition to contributing to significant expenses in Infections originating from C. albicans have been observed 1 public health. Among the possible etiologic agents, Candida since the time of Hippocrates, who described Candida dis- spp. are noted due to their relevance and prevalence. Accord- 4 eases in debilitated patients in 337 B.C. Now, Candida spp. ing to McCarty and Pappas (2015), 15–20 microorganisms from are responsible for the majority of blood infections in inten- 2 the genus Candida are described as certain to cause infection. sive therapy units around the world, impacting hospitalization 5 times and costs. In 2005, for example, the Centers for Disease ∗ Control and Prevention (CDC) showed that for each diagno- Corresponding author. sis of Candida spp. infection, the period of hospitalization E-mail: [email protected] (L.O. Felipe). https://doi.org/10.1016/j.bjm.2017.05.008 1517-8382/© 2017 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 9 (2 0 1 8) 212–219 213 12 is lengthened from 3 to 13 days. Financially speaking, this validated treatments. The doctor Paracelsus is considered additional period leads to expenses from $6000 to $29,000. the founder of plant-based medicine due to his great contrib- 13 Furthermore, each year, these values are estimated to reach utions in the field. His findings, along with those of other 6,7 approximately $8 billion. researchers, led to a consolidation of knowledge in the field of Advances in medicine have enabled people who are natural products and created other domains such as pharma- immune suppressed (such as those who have received organ cognosy. Among the medicinal properties of natural products, 8 transplants or are HIV positive) to live longer lives. The great- one can find anti-inflammatory, antispasmodic, anticancer, est vulnerability of such individuals is to metabolically flexible antimutagenic, antibacterial, antifungal, antiviral and vermi- 14 microorganisms of the genus Candida, which have increased cidal properties. the rate of morbidity and mortality to 35% in this group of Essential oils compose the most utilized group of sub- 9 people. In addition, parallel to the increasing number of stances. Isolated from plants, essential oils are compounds cases of fungal infection caused by Candida spp., the resis- largely described in the scientific literature as versatile in 15 tance of Candida spp. to antimicrobial drugs has progressively the treatment of many infirmities. Their active ingredients increased. The latter fact has sparked the attention of the are usually various terpenes, which are secondary metabo- World Health Organization (WHO) due to its relevance and led lites excreted by vegetables to expel predators or harmful 16 to the release of the report Antimicrobial Resistance: Global Report agents. One example of a bioactive essential oil is the one 10 Surveillance. obtained from Melaleuca alternifolia leaves; the activity of this 17 The development of resistance in Candida spp., from ther- oil is attributed to terpinen-4-ol, a monoterpene. apy with amphotericin B, against drugs from the azole group, The isolation of bioactive molecules is also performed on echinocandin and fluconazole was among the key informa- natural sources other than vegetable cells. Some metabolites tion provided in this report, along with reports of cases of produced by microorganisms are also important sources of 18 multiresistance from different regions of the world such as new bioactive substances. In Table 1, therapeutic agents 10 Asia and the Middle East and some areas of South America. obtained through bioprospection are presented; these agents These data are alarming because such resistance has devel- are responsible for significant impact on the medicinal treat- oped against antifungal drugs widely used to combat fungal ments that have been offered in recent years. diseases worldwide. Amphotericin B, for example, is a classical In addition to the compounds listed in Table 1, lactoferrin (a antifungal drug, and in many countries, it is the only medicine peptide isolated from milk) and chitosan (a copolymer derived available for the treatment of fungal infections. from chitin) also show distinct biological activity, includ- 19 The azoles have been administered in formulations ing antioxidant, anti-allergy and antimicrobial actions. The that combine different groups of chemotherapeutic drugs, association of such natural products with other antimicrobial attempting to overcome the increase in microbial resis- drugs has been recently investigated to identify a possible syn- tance. This fact impacts both the cost and the success of ergistic effect. This can provide alternative treatments against treatments against that type of infection. Finally, the devel- multiresistant microorganisms, thereby reducing the amount opment of resistance to fluconazole—the most commonly of drugs used in treatments, which can impact drug-resistance used antifungal—drastically varies according to the Candida phenomena. spp. and from country to country. For example, the inten- However, as noted by Harvey et al. (2015), due to sity of the multiresistance in Candida spp. to fluconazole is the environmental legislation that protects biodiversity, higher in Denmark (33%) and lower in the Korean Republic bioprospection, among other pursuits, has suffered a consid- 10 20 (0.9%). Therefore, the aim of this paper is to discuss the most erable slowdown in the last 20 years. The reduction in the promising substances available for candidiasis treatment. In rate of drug discovery and new medicines provided by the addition, this work reinforces the importance of using natural pharmaceutical industry reflects such constraints. products along with those medicines traditionally employed Bioprospection is a feasible way to discover new in the treatment of such infections. biomolecules. One example of such a discovery is teixobactin, 21 which was isolated from soil samples by Ling et al. (2015). This molecule proved to be very promising as a new antibiotic Natural products class because its administration in mice was able to suc- cessfully eliminate infections caused by Staphylococcus aureus Natural products have been widely used in society since super bacteria strains. Therefore, after nearly 30 years with- 11 3500 B.C. Medicinal methods range from folk medicine to out a new drug discovery, this promising molecule—found Table 1 – Conventional medicines originally obtained from natural sources. Active compound Source Type Indication/Use Artemisinin Artemisia annua Plant Antimalarial Lovastatin diseases Aspergillus terreus Microbial Hypercholesterolemia/cardiovascular Micafungin Coleophoma empetri Microbial Antifungal Paclitaxel Taxus brevifolia Plant Anti-tumor Reserpine Rauwolfia serpentina Plant Hypertension/Raynaud phenomenon 214 b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 9 (2 0 1 8) 212–219 Table 2 – Types of infection described for candidiasis and its respective places of occurrence. Type of candidiasis Location of occurrence 32–34 Mucocutaneous Oral, vaginal, penile (balanitis). 35 Cutaneous Moisturized parts of body: areas close to breast, armpits, fold of groin and under the nails. 5 Systemic (candidemia) Visceral dissemination: lungs, meninges, kidney, bladder, joints, liver, heart and eyes. drugs. Nephrotoxicity (especially in amphotericin administra- Table 3 – Different classes of antifungals that are tion), nausea/vomiting and stomachache are among the main available on the market. effects. Azoles Echinocandins Pyrimidines Polienics In addition to side effects, another major challenge in the Cetoconazole Anidulafungin Flucytosine Amphotericin-B campaign against Candida spp.