Antifungal activity of 2-chloro-N-phenylacetamide: a new molecule with fungicidal and antibiofilm activity against fluconazole-resistant Candida spp

Abstract In the current context of emerging drug-resistant fungal pathogens such as Candida albicans and Candida parapsilosis, discovery of new antifungal agents is an urgent matter. This research aimed to evaluate the antifungal potential of 2-chloro-N-phenylacetamide against fluconazole-resistant clinical strains of C. albicans and C. parapsilosis. The antifungal activity of 2-chloro-N-phenylacetamide was evaluated in vitro by the determination of the minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), inhibition of biofilm formation and its rupture, sorbitol and ergosterol assays, and association between this molecule and common antifungal drugs, amphotericin B and fluconazole. The test product inhibited all strains of C. albicans and C. parapsilosis, with a MIC ranging from 128 to 256 µg.mL-1, and a MFC of 512-1,024 µg.mL-1. It also inhibited up to 92% of biofilm formation and rupture of up to 87% of preformed biofilm. 2-chloro-N-phenylacetamide did not promote antifungal activity through binding to cellular membrane ergosterol nor it damages the fungal cell wall. Antagonism was observed when combining this substance with amphotericin B and fluconazole. The substance exhibited significant antifungal activity by inhibiting both planktonic cells and biofilm of fluconazole-resistant strains. Its combination with other antifungals should be avoided and its mechanism of action remains to be established.

Resumo No atual contexto de patógenos fúngicos resistentes emergentes tais como Candida albicans e Candida parapsilosis, a descoberta de novos agentes antifúngicos é uma questão urgente. Esta pesquisa teve como objetivo avaliar o potencial antifúngico da 2-cloro-N-fenilacetamida contra cepas clínicas de C. albicans e C. parapsilosis resistentes a fluconazol. A atividade antifúngica da substância foi avaliada in vitro através da determinação da concentração inibitória mínima (CIM), concentração fungicida mínima (CFM), ruptura e inibição da formação de biofilme, ensaios de sorbitol e ergosterol, e associação entre esta molécula e antifúngicos comuns, anfotericina B e fluconazol. O produto teste inibiu todas as cepas de C. albicans e C. parapsilosis, com uma CIM variando de 128 a 256 µg.mL-1, e uma CFM de 512-1,024 µg.mL-1. Também inibiu até 92% da formação de biofilme e causou a ruptura de até 87% de biofilme pré-formado. A 2-cloro-N-fenilacetamida não promoveu atividade antifúngica pela ligação ao ergosterol da membrana celular fúngica, tampouco danificou a parede celular. Antagonismo foi observado ao combinar esta substância com anfotericina B e fluconazol. A substância exibiu atividade antifúngica significativa ao inibir tanto as células planctônicas quanto o biofilme das cepas resistentes ao fluconazol. Sua combinação com outros antifúngicos deve ser evitada e seu mecanismo de ação deve ser estabelecido.

Antifungal activity of 2-chloro-N-phenylacetamide: a new molecule with fungicidal and antibiofilm activity against fluconazole-resistant Candida spp / Atividade antifúngica de 2-cloro-N-fenilacetamida: uma nova molécula com atividade fungicida e anti-biofilme contra Candida spp. resistentes a fluconazol

In the current context of emerging drug-resistant fungal pathogens such as Candida albicans and Candida parapsilosis, discovery of new antifungal agents is an urgent matter. This research aimed to evaluate the antifungal potential of 2-chloro-N-phenylacetamide against fluconazole-resistant clinical strains of C. albicans and C. parapsilosis. The antifungal activity of 2-chloro-N-phenylacetamide was evaluated in vitro by the determination of the minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), inhibition of biofilm formation and its rupture, sorbitol and ergosterol assays, and association between this molecule and common antifungal drugs, amphotericin B and fluconazole. The test product inhibited all strains of C. albicans and C. parapsilosis, with a MIC ranging from 128 to 256 µg.mL-1, and a MFC of 512-1,024 µg.mL-1. It also inhibited up to 92% of biofilm formation and rupture of up to 87% of preformed biofilm. 2-chloro-N-phenylacetamide did not promote antifungal activity through binding to cellular membrane ergosterol nor it damages the fungal cell wall. Antagonism was observed when combining this substance with amphotericin B and fluconazole. The substance exhibited significant antifungal activity by inhibiting both planktonic cells and biofilm of fluconazole-resistant strains. Its combination with other antifungals should be avoided and its mechanism of action remains to be established.

No atual contexto de patógenos fúngicos resistentes emergentes tais como Candida albicans e Candida parapsilosis, a descoberta de novos agentes antifúngicos é uma questão urgente. Esta pesquisa teve como objetivo avaliar o potencial antifúngico da 2-cloro-N-fenilacetamida contra cepas clínicas de C. albicans e C. parapsilosis resistentes a fluconazol. A atividade antifúngica da substância foi avaliada in vitro através da determinação da concentração inibitória mínima (CIM), concentração fungicida mínima (CFM), ruptura e inibição da formação de biofilme, ensaios de sorbitol e ergosterol, e associação entre esta molécula e antifúngicos comuns, anfotericina B e fluconazol. O produto teste inibiu todas as cepas de C. albicans e C. parapsilosis, com uma CIM variando de 128 a 256 µg.mL-1, e uma CFM de 512-1,024 µg.mL-1. Também inibiu até 92% da formação de biofilme e causou a ruptura de até 87% de biofilme pré-formado. A 2-cloro-N-fenilacetamida não promoveu atividade antifúngica pela ligação ao ergosterol da membrana celular fúngica, tampouco danificou a parede celular. Antagonismo foi observado ao combinar esta substância com anfotericina B e fluconazol. A substância exibiu atividade antifúngica significativa ao inibir tanto as células planctônicas quanto o biofilme das cepas resistentes ao fluconazol. Sua combinação com outros antifúngicos deve ser evitada e seu mecanismo de ação deve ser estabelecido.

Interpretation of 2022 World Health Organization fungal priority pathogens list / 中华实用儿科临床杂志

The global morbidity of invasive fungal diseases (IFD) tends to increase, especially in immunocompromised people.Due to the atypical symptoms, unclear etiological mechanism, and emerging antifungal resistance, IFD challenge current clinical diagnosis and treatment.The World Health Organization (WHO) developed the first WHO fungal priority pathogens list in 2022.The most concerning fungal pathogens were listed and summarized to promote further understanding of the epidemiology of IFD and antifungal drug resistance.It is hoped to provide a basis for the prevention and interventions of IFD.

Distribution and antifungal susceptibility of Candida species isolated from clinical samples in southern Brazil

Abstract Invasive infections caused by Candida species have been strongly associated with poor prognosis and high resistance rates to some antifungals. This study aimed to identify Candida species isolated from different anatomical sites and to describe their susceptibility profile to antifungals. Ninety-four clinical isolates of Candida were obtained from a Medical Laboratory of Santa Catarina/Brazil. Species identification was performed by MALDI-TOF MS. Susceptibility assays were performed as described by Clinical Laboratory Standard Institute (CLSI) microboth method. Among the analyzed samples, C. albicans was the pathogen most incident (59.9%) followed by C. parapsilosis complex (14.9%), C. glabrata complex (8.5%), and C. tropicalis (6.3%). 37 Candida strains were isolated from vaginal content (39.3%), 21 from the nail (22.4%), 8 from tracheal aspirates (8.5%), and 7 from urine (7.4%). Together, the Candida isolates presented decreased susceptibility to azole drugs, mainly to fluconazole and itraconazole. Amphotericin B showed sensibility in 95.7% of samples analyzed. Previous knowledge about etiology and antifungal susceptibility becomes indispensable to conduct an efficient treatment.

Trend of Prevalence and Antifungal Drug Resistance of Candida Species Isolated from Candidemia Patients at a Tertiary Care Hospital During Recent Two Decades / 대한임상미생물학회지

BACKGROUND: Candidemia has increased with an increasing number of people in the high risk group and so has become more important. This study was conducted to investigate the isolation rate of Candida species from candidemia patients and the change in rate of antifungal resistance. METHODS: At a single tertiary care hospital, 1,120 blood cultures positive for Candida species from 1997 to 2016 were investigated according to date of culture, gender, age, and hospital department. RESULTS: During the investigation period, the number of candidemia patients increased from 14 in 1997 to 84 in 2016. The most common organism identified during the two decades was Candida albicans (40.8%), followed by Candida parapsilosis (24.1%), Candida tropicalis (13.2%), and Candida glabrata (12.8%). C. glabrata was relatively common in females (45.5%) compared to males. The age group 40-89 years was more frequently infected than other age groups, and the most frequent isolates according to age group were C. albicans in neonate (66.7%), C. parapsilosis in 1-9-year-olds (41.7%), and C. glabrata in those aged ≥60 years (range; 13.3%–20.0%). According to the visited departments, C. albicans, C. glabrata, and Candida haemulonii were more common in medical departments, while C. parapsilosis was more common in surgical departments. In the antifungal susceptibility test, a rising trend of azole resistance among C. albicans and C. glabrata was observed in recent years. CONCLUSION: In this study, it was confirmed that the isolation rate of Candida species in blood is different by age, gender, and hospital department, and the distribution of isolated Candida species changed over time. The resistance patterns of antifungal agents are also changing, and continuous monitoring and proper selection of antifungal agents are necessary.

Research Review on Antifungal Drug Resistance Mechanisms in Candida Spp / 现代检验医学杂志

In recent years,the epidemiology of Candida infection has changed.Although Candida albicans is still the main pathogens causing invasive candidiasis,non-albicans Candida species are increasingly encountered.Different Candida species show distinct sensitivity of different drugs.The emergence of drug resistance has become the main problem of Candida in-fection treatment.Antifungal resistance of clinical Candida infections often lead to treatment failure.The review of resistance mechanisms and the effect on clinical treatment is very significant to improve the prognosis of patients and strengthen the control of infection.This text reviews the present state of the detection of mechanisms of resistance in Candida spp .

The activity of echinocandins, amphotericin B and voriconazole against fluconazole-susceptible and fluconazole-resistant Brazilian Candida glabrata isolates

The extensive use of azole antifungal agents has promoted the resistance of Candida spp to these drugs. Candida glabrata is a problematic yeast because it presents a high degree of primary or secondary resistance to fluconazole. In Brazil, C. glabrata has been less studied than other species. In this paper, we compared the activity of three major classes of antifungal agents (azoles, echinocandins and polyenes) against fluconazole-susceptible (FS) and fluconazole-resistant (FR) C. glabrata strains. Cross-resistance between fluconazole and voriconazole was remarkable. Among the antifungal agents, the echinocandins were the most effective against FS and FR C. glabrata and micafungin showed the lowest minimal inhibitory concentrations.

Antifungal Resistance in Yeasts and Filamentous Fungi / 감염과화학요법

The incidence of invasive fungal infection has increased worldwide along with the increasing population of high risk patients. Recently developed antifungal agents, such as second-generation triazoles and echinocandins, provide the potential to improve therapeutic options against invasive fungal infections. However, treatment of invasive fungal infections has been hampered by both intrinsic and acquired resistance to antifungal agents among many fungal pathogens. A better understanding of the clinical impact of antifungal resistance is important for selecting the proper antifungal agent in patients with systemic fungal infections. This article reviews the current situation with regard to intrinsic and acquired resistance of clinically significant yeasts and filamentous fungi against currently available antifungal agents.

Antifungal Resistance in Yeasts and Filamentous Fungi / 감염과화학요법

The incidence of invasive fungal infection has increased worldwide along with the increasing population of high risk patients. Recently developed antifungal agents, such as second-generation triazoles and echinocandins, provide the potential to improve therapeutic options against invasive fungal infections. However, treatment of invasive fungal infections has been hampered by both intrinsic and acquired resistance to antifungal agents among many fungal pathogens. A better understanding of the clinical impact of antifungal resistance is important for selecting the proper antifungal agent in patients with systemic fungal infections. This article reviews the current situation with regard to intrinsic and acquired resistance of clinically significant yeasts and filamentous fungi against currently available antifungal agents.

In Vitro Susceptibilities of Clinical Isolates of Aspergillus Species against Echinocandins / 감염과화학요법

BACKGROUND: Echinocandins are a new class of antifungal agents with potent in vitro and in vivo activities against Aspergillus species. We investigated the in vitro activity of caspofungin and micafungin against Korean clinical Aspergillus isolates. MATERIALS AND METHODS: A total of 100 clinical isolates of Aspergillus species (32 A. fumigatus, 26 A. flavus, 22 A. niger and 20 A. terreus) were tested. The susceptibilities of caspofungin, micafungin, amphotericin B and itraconazole were established by means of the Clinical and Laboratory Standards Institute (CLSI) M38-A microdilution methods. The results for caspofungin and micafungin were evaluated by using the end points of minimum inhibitory concentrations (MIC) and minimum effective concentration (MEC, the lowest concentration that produces short and aberrant hyphal branchings microsopically). RESULTS: The MEC ranges of caspofungin and micafungin against 100 isolates of Aspergillus species were 0.06 to 0.5 microgram/mL and 16 microgram/mL unexpectedly, in 5% (5/100) and 4% (4/100) of isolates, respectively, which resulted in the loss of a consistent correlation between the two endpoint readings. The MEC50 of all Aspergillus isolates for caspofungin and micafungin were 0.25 and < or =0.03 /mL, respectively, and the MIC50 for amphotericin B and itraconazole were 0.5 and 0.25 microgram/mL, respectively. There were no species-related differences in caspofungin and micafungin MECs for Aspergillus species. CONCLUSION: This data demonstrates excellent in vitro activity of echinocandins against clinical strains of Aspergillus species.

In Vitro Susceptibilities of Clinical Isolates of Aspergillus Species against Echinocandins / 감염과화학요법

BACKGROUND: Echinocandins are a new class of antifungal agents with potent in vitro and in vivo activities against Aspergillus species. We investigated the in vitro activity of caspofungin and micafungin against Korean clinical Aspergillus isolates. MATERIALS AND METHODS: A total of 100 clinical isolates of Aspergillus species (32 A. fumigatus, 26 A. flavus, 22 A. niger and 20 A. terreus) were tested. The susceptibilities of caspofungin, micafungin, amphotericin B and itraconazole were established by means of the Clinical and Laboratory Standards Institute (CLSI) M38-A microdilution methods. The results for caspofungin and micafungin were evaluated by using the end points of minimum inhibitory concentrations (MIC) and minimum effective concentration (MEC, the lowest concentration that produces short and aberrant hyphal branchings microsopically). RESULTS: The MEC ranges of caspofungin and micafungin against 100 isolates of Aspergillus species were 0.06 to 0.5 microgram/mL and 16 microgram/mL unexpectedly, in 5% (5/100) and 4% (4/100) of isolates, respectively, which resulted in the loss of a consistent correlation between the two endpoint readings. The MEC50 of all Aspergillus isolates for caspofungin and micafungin were 0.25 and < or =0.03 /mL, respectively, and the MIC50 for amphotericin B and itraconazole were 0.5 and 0.25 microgram/mL, respectively. There were no species-related differences in caspofungin and micafungin MECs for Aspergillus species. CONCLUSION: This data demonstrates excellent in vitro activity of echinocandins against clinical strains of Aspergillus species.

Distribution pattern of fungal pathogens and their antibiotic resistance in autoimmune disease patients with fungal infection / 中国医师进修杂志

Objective To identify the most common fungal pathogens and their antifungal drug resistance in autoimmune disease (AD) patients with fungal infection , for guiding the rational use of antifungal therapy. Methods The identification were analyzed by ATB Expression automatic microbiology analytical instrument system. The antifungal susceptibility test was done by ATB FUNGUS strip. Results Of 428 patients studied,36(8.4%) had fungal infections. The most commonly infective sites were lower respiratory tract(53.5%),urinary tract(20.9%), intestinal tract(11.6%). A total of 43 fungi strains were isolated, the most common fungi were Candida albicans (65.1%), Candida glabrata (11.6%), Candida tropicalis (7.0%),and Candida parapsilosis (4.7%).Resistance rates of Candida albicans against ketoconazole, miconazole and econazole were 35. 7% , 46.4% and 32.1% , while resistance rates to fluconazole, amphotericin B, nystain and flucytosine were much lower, being 0, 14.3% , 14.3% and 7.1% . The resistance rates of other fungi were similar to Candida albicans. Conclusion The main pathogens causing fungal infection in patients with AD is Candida albicans. It should as early as possible process the clinical antifungal therapy under the result of antifungal susceptibility test and supportive measure.