The frequent and improper use of antibiotics has resulted in the rise of multi-drug resistant (MDR) bacteria. Currently, it is estimated that infections caused by antibiotic-resistant bacteria are responsible for approximately 70,000 deaths globally each year. Without the development of new treatments, MDR bacterial infections could lead to an additional 10 million deaths annually by 2050, surpassing the mortality rate of cancer(Piddock, 2016). On a global scale, deaths associated with antibiotic resistance rank Staphylococcus aureus as the second leading killer in the world (Murray et al., 2022). Numerous diseases, such as sepsis, bacteremia, osteomyelitis, endocarditis, skin abscesses, wound infections, and deep tissue abscesses, are caused by S. aureus (Lowy, 1998).
According to data from the 1970s, methicillin-resistant S. aureus (MRSA) was the primary cause of a marked rise in morbidity and healthcare-associated expenses in the United States (Haley et al., 1982).Hospitals worldwide are already experiencing enormouscases of MRSA, and the advent of community-associated (CA) MRSA has raised even more serious concerns (Kim et al., 2002). In the United States, the majority of clinical S. aureus isolates (95%) exhibit resistance to penicillin, and more than half are methicillin-resistant. Similarly, the prevalence of MRSA is a significant issue in Europe (System, 2003; Tiemersma et al., 2004).
In 2005, Vancomycin-intermediate S. aureus (VISA) strains were considered rare. However, a Turkish study found that 46 out of 256 (18%) MRSA samples collected from blood and pus between 1998 and 2002 exhibited the VISA phenotype, indicating that the prevalence of VISA strains was becoming alarming (Sancak et al., 2005). More recently, the emergence of vancomycin-resistant S. aureus (VRSA) isolates, which exhibit complete vancomycin resistance, is even more concerning (Gardete et al., 2008; Kacica et al., 2004; Tenover et al., 2004). The increased use of vancomycin to treat MRSA has led to heightened vancomycin selective pressure within the community, contributing to the emergence of more VISA and VRSA strains (Appelbaum 2006; Lomba et al., 2010).
The first glycopeptide antibiotic identified as vancomycin, offers one of the empirical treatments for MRSA infections and continues to be a cornerstone in this regard (Bamigboye et al., 2018). The first VISA from Japan was reported in 1997, having a minimum inhibitory concentration (MIC) of 8 µg/ml. Concurrently, from clinical specimens, S. aureus isolates with a heterogeneous (h)VISA phenotype (Mu3) was identified (Hiramatsu et al., 1997). The first instance of VRSA in a diabetic patient was documented in the United States in 2002 (Goldrick, 2002). The majority of research on VISA/hVISA has concentrated on drug resistance; however, further research is needed to determine how virulent VISA/hVISA is in comparison to vancomycin-sensitive S. aureus (VSSA), even though VISA is known to have a thicker cell wall (Cui et al.,2000; Howden et al., 2006; Katayama et al., 2009). MICs in the susceptible range (≤ 2 µg/mL) are displayed by hVISA, yet they also have a subpopulation that exhibits a resistant phenotype (Chen et al., 2011; Charles et al., 2004).
Earlier in vitro research revealed a number of potential pathways for vancomycin resistance in MRSA, the primary one being the cell wall's increased thickness and lower permeability, which reduces vancomycin's availability for intracellular target molecules. Plasmid-mediated vancomycin resistance genes (vanA, vanB, vanD, vanE, vanF, and vanG) may have been transferred from enterococcal species, resulting in another type of resistance (Hiramatsu et al., 1997; Francia et al., 2002; Tenover et al., 2001; Woodford, 2001). Higher rates of vancomycin treatment failure are linked to infections caused by VISA and hVISA, which are also linked to longer hospital stays, a higher risk of persistent infections, and higher treatment costs (Charles et al., 2004; Maor et al., 2009). In order to solve this problem, the current study looked into the potential causes of chronic infection by VISA as well as the capacity of VISA and VSSA strains to infect or colonize skin and soft tissue (Jin et al., 2020).
Oritavancin (a semisynthetic glycopeptide), complestatin, and corbomycin (both glycopeptides of the type V family) have been found to be effective against MRSA and VRSA strains (Zhanel et al., 2012; Culp et al., 2020). These glycopeptides work against the S. aureus cell wall through a variety of methods, such as the suppression of fatty acid synthesis and peptidoglycan formation (Zhanel et al., 2012; Culp et al., 2020). Despite these options, S. aureus-resistant strains can possess a broad range of resistance mechanisms, making it difficult to control them with the standard antibiotics currently available to treat the illnesses they cause (Jubeh et al., 2020). Given the circumstances, it is imperative to look for and develop novel antimicrobial alternatives to fight antibiotic-resistant bacterial strains likeS. aureus strains, particularly VRSA strains, which pose a serious threat to the public's health worldwide (World Health Organization, 2021).
To address the issue of increasing bacterial resistance, antimicrobial peptides (AMPs) are a promising alternative to traditional antibiotics, showing significantly higher efficacy in killing resistant strains (Omardien et al., 2016; Yu et al., 2018;Singh et al.,2023; Anurag Anand et al., 2023). AMPs offer a potent solution for managing both antibiotic-susceptible, intermediate, and resistant bacteria, addressing serious human health threats (Bédard et al., 2019; Fan et al., 2011). AMPs are natural molecules, produced by the innate immune systems of various organisms and serve as an effective defense against infections caused by bacteria, fungi, viruses, and certain protozoa (Wang et al., 2016). AMPs possess a diverse array of action mechanisms, enabling them to impact various targets of bacteriaincluding bacterial membrane damage, inhibition of protein, enzyme, and nucleic acid synthesis at the cytoplasmic level, as well as modifications to protein folding (Powers and Hancock, 2003; Yeung et al., 2011; Park et al., 1998).
To date, many AMPs have been discovered, demonstrating activity against multiple pathogenic microbes, including those that are resistant (Lei et al., 2019).Those kinds of data are already available in the literature and are more structurally available in generalized AMP databases which includeDRAMP 3.0 (Shi et al., 2022), APD3 (Wang et al., 2016),AMPDB v1 (Mondal et al., 2023), CAMP R4 (Gawde et al., 2023), DBAASP v3 (Pirtskhalava et al., 2021), dbAMP 2.0 (Jhong et al., 2022) and specilised AMP databases include Peptaibols (Whitmore and Wallace, 2004), LAMP (Zhao et al., 2013),MilkAMP (Théolier et al., 2014),BACTIBASE (Hammami et al., 2010), PhyTAMP (Hammami et al., 2009), RAPD (Li et al., 2008), ANTISTAPHYBASE (Zouhir et al., 2017), DADP (Novković et al., 2012), BaAMPs (Di Luca et al., 2015),AVPdb (Qureshi et al., 2014),SAPdb (Mathur et al., 2021),DRAVP (Liu et al., 2023),Defensins Knowledgebase (Seebah et al., 2007), InverPep (Gómez et al., 2017), YADAMP (Pitto et al., 2012),HIPdb (Qureshi et al., 2013), ANTIPSEUDOBASE (Zouhir et al., 2023), TAMRSAR (TAMRSAR, 2024). Generalized databases list all AMPs, while specialized databases focus on specific AMPs targeting particular organisms or for other perspectives.
Both generalized and specialized databases contain AMPs that can target S. aureus. However, these databases have very limited/no AMPs available specifically for targeting VRSA, VISA, and VSSA. Among the specialized databases, ANTISTAPHYBASE (Zouhir et al., 2017) (currently retired) and our own developed TAMRSAR (TAMRSAR, 2024) (specific to MRSA strains only) are dedicated to AMPs and essential oils (EOs) targeting S. aureus strains. To date, no single database provides comprehensive information on AMPs that can target VRSA, VISA, and VSSA, although these forms of S. aureus cause infections easily and have limited treatment options available (Cong et al., 2020).Several AMPs have been reported to demonstrate strong activity against VRSA, VISA, and VSSA (Hernández-Aristizábal et al., 2021), but no resource amalgamates all this information in an easily accessible manner. With this in mind, we developed a fully specialized knowledgebase namedAnti-Vancomycin-Resistant/Intermediate/Susceptible S. aureusPeptide Database(AVR/I/SSAPDB), dedicated to AMPs that can target VRSA, VISA, and VSSA. We hope this resource will be helpful to the scientific community and pharmaceutical industries in studying and developing new peptide-based therapeutics against VRSA, VISA, and VSSA.