A review on mechanism of Bacteria resisting plant antibiotics

Introduction

Antibiotic is a Greek word made up of two words "Anti" means fighting or killing and "bios" means life i.e it means 'life killing'. According to Waksman's classical definition, an antibiotic is "a compound produced by a microbe with growth-inhibiting or killing activity against other microbes" (Davies and Davies, 2010) [13] . The majority of antibiotics currently in use have their origin in the phylum Actinobacteria, with soil-dwelling bacteria of the genus Streptomyces producing over 80% of actinobacterial-derived antibiotics (Barka et al., 2016). Prior to the discovery of naturally occurring antibiotics, sulfa drugs, quinolones, salvarsan, and other synthetic chemicals were used as chemotherapy agents (Aminov, 2010). The most frequent ways that antibiotic resistance develops in bacteria are either by mutating a target-site protein, acquiring an antibiotic-resistance gene (ARG) that gives resistance by effluxing or inactivating the antibiotic, or synthesising a new target protein that is resistant to the antibiotic (Davis and Davis, 2010) [13] . Studies on antibiotic resistance in animal agriculture and human pathogens have yielded a wealth of information. The capacity of bacterial pathogens to obtain ARGs and combine them into transferable DNA blocks encoding multiple ARGs has led to important problems that have an impact on the efficaciousness of treatment interventions intended to address certain distinct human infections. A swift evolutionary response to the millions of kilograms of antibiotics that human use annually has been sparked by basic mechanism of population dynamics and microbial ecology, which have contributed to the existing worldwide crisis of bacterial populations resistant to antibiotics. The fact that ARGs were already present in bacterial populations was not known when antibiotics were discovered and used in clinical medicine (Perry et al., 2016) [42] . Furthermore, numerous sophisticated investigations determining the microbial antibiotic resistance have revealed information that was not known 70 years ago about the the degree to which ARGs may be transferred from one bacterium to another, even between species that are phylogenetically different. The term "antibiotic resistome" refers to the entire microbial genome that contains all known ARGs (Wright, 2007) [65] . Conceptually, the most significant aspect of the antibiotic resistome is that individual ARGs may be accessed by all bacteria. Thus, this review has focused on the perspectives that can deal with the challenges that spring up by the spread of resistance among bacteria.

History

In 1928, the fungus Penicillium inadvertently contaminated a culture plate in Alexander Fleming's laboratory which apparently lead to the discovery of first naturally occurring antibiotic Penicillin. However, penicillin was not commercialised until the late 1930s as it prevented the formation of cell walls and proved highly effective against Gram-positive bacteria but on the other side, it was ineffective against Gram-negative bacteria (because of the outer membrane) and tubercle bacillus (because of its unusually thick cell wall). The next major finding was in 1943 with the discovery of streptomycin isolated by Streptomyces griseus. The major advantage of this discovery was that streptomycin was efficient against both tubercle bacillus and Gram-negative bacteria. It suppressed protein synthesis by binding to the 30S component of the bacterial ribosome (Hopwood, 2007) [21] . This was the golden period (1940-1990) for paving a way to antibiotic research and development that followed with the discovery of soil bacteria that produced chloramphenicol and tetracycline and revolutionised the field of antibiotics between years 1945 and 1955. After this period, researchers began examining the effects of antibiotics outside of the medical field based on their application. Brown and Boyle (1944) contributed to the plant disease management by effectively using penicillin to treat crown gall disease incited by multiple bacteria. Upjohn in 1946 from the United States discovered that cycloheximide had strong anti-fungal activity against plant infections. Following the suse of these antibiotics, it was discovered that streptomycin and chloramphenicol had an effective influence on the management of bacterial and fungal infections (Clardy et al., 2009) [10] . Out of the approximately 900 types of antibiotics whose chemical structures have been studied, just over ten types have been found to have a practical use in agriculture. Blasticidin was successfully developed by the Japanese company Hokko Chemical in 1955 followed by kasugamycin by 1963. These two antibiotics were used extensively to treat rice blast disease, which is caused by Pyricularia grisea. In 1972, Takeda Pharmaceutical Company created validamycin, a treatment for rice sheath blight (Rhizoctonia solani). The same pharmaceutical company created midiomycin by the end of 1970 to successfully treat powdery mildew disease in significant crops. Along with Jinggangmycin, China was a major producer of the antibiotics blasticidin, kasugamycin, and polyoxin. In 1982, the Jilin Academy of Agricultural Sciences' Plant Protection Institute made significant progress in the development of gongzhulingmycin, primarily for the management of Ustilagocrameri, Tilletiafoetida, stinking bunt, and sorghum covered smut (Valarmathi, 2020) [61] . The first public sector pharmaceutical manufacturing company established by the Indian government is Hindustan Antibiotics Limited (HAL), with its headquarters located in Pimpri, India.

Antibiotics use in plant agriculture

The huge amount of bacterial pathogen population on susceptible host with the scarcity of bactericides make treatment of plant diseases challenging but the antibiotics have proven to be the most effective alternative for bacterial disease control in many pathosystems when robust and lasting host disease resistance is lacking. This is because antibiotics reduce the size of the bacterial population and prevent disease outbreaks but the use was restrained by a number of factors, combining phytotoxicity problems at larger dosages and their lack of effectiveness at lower ones and higher cost when in comparison to other accessible techniques for preventing illness. Consequently, most common antibiotic used worldwide to control plant diseases is streptomycin, which targets pathogens like X. campestris causing bacterial spot on tomatoes and peppers, Erwinia amylovora causing fire blight on apple and pear and P. syringae infecting apple and pear trees', flowers and fruits. In certain disease control scenarios, such as the management of X. arboricola pv. pruni, the causal agent of bacterial spot on peaches and nectarine, oxytetracycline has been employed as the principal antibiotic (McManus et al., 2002) [31] . Furthermore, in the United States, oxytetracycline has been employed as a supplementary antibiotic to address fire blight, particularly in cases where streptomycin resistance has been an issue. After the environment is exposed to the antibiotic solution, it is adversely affected by temperature, sunlight (both visible and UV), rainfall, and other particular elements of the phyllosphere that could impact adsorption, regardless of whether it reaches the target (Sundin and Wang, 2018) [60] .

Effect of antibiotic application on the microbiome

Most of the antibiotics are applied as spray on the plants. According to estimates, air blast sprayers lose between 44% and 71% of the spray solutions applied to the environment. If provided during the bloom phase, antibiotics that reach the target areas in the tree canopy have an effect on the microbiomes of the phyllosphere and flowers. The antibiotic may also be consumed by insects that are feeding in the tree canopy, which may have an effect on the gut microbiome of the insects. When applying antibiotic spray on trees, some of the spray may drift and not reach the target, or it may be lost to drainage from rain or spraying operations (Sundin and Wang, 2018) [60] . Following the release of the antibiotic solution into the surroundings, it is adversely affected by temperature, sunlight (both visible and UV), rainfall and other particular elements of the plant such as environment of leaf that could impact adsorption, regardless of whether it reaches the target. Some antibiotics drift to other plants and grasses which are grazed by animals and affect gut microbiota of animals (Fig. 1). According to study conducted by Scherer et al. (2013) [52] , it was recorded that the proportion of E. coli isolates resistant to streptomycin found in the feaces of sheep grazing on a pasture sprayed with the antibiotic was found to rise (from 14.7% to 39.9% compared to 15.8% to 22.3% in a control group). Antibiotics drifted from target can also affect phyllosphere and rhizosphere microbiome and develop resistance against antibiotics. Yashiro and McManus (2012) [67] observed that phyllosphere bacteria isolated from streptomycin sprayed orchard continuously for ten years exhibited less resistance than non-sprayed orchard against streptomycin. [11] . The E. coli AcrAB/TolC efflux pump is a well-studied example of an intrinsic resistance mechanism. It can export different classes of antibiotics, detergents, dyes and disinfectants and has very broad substrate specificity (Nikaido and Takatsuka, 2009) [33] . Another instance of intrinsic resistance that results from the outer membrane's permeability barrier is vancomycin resistance found in E. coli and other Gramnegative bacteria (Arthur and Courvalin, 1993) [2] . Conversely, acquired resistance mechanisms are typically acquired through horizontal gene transfer (HGT). These mechanisms comprise enzymes which can alter antibiotic or its target, as well as plasmid-encoded specific efflux pumps (Fig 2 ), like S. aureus TetK and TetL (van Hoek et al., 2011) [62] . An extensively recorded instance of this phenomenon is the mobilisation of the chromosomal βlactamase gene ampC to a plasmid, which leads to its global spread (Dantas and Sommer, 2012) [12] .

Origin of antibiotic-resistant bacterial pathogens

The three main sources of antibiotic resistance that are currently known to exist in bacterial pathogens are mutations encoding target-site alterations, the existence of resistance genes within the microbiome, their eventual transfer to pathogenic species subject to antibiotic selection, and the horizontal gene transfer mechanism used by antibiotic-producing microorganisms to release their naturally occurring resistance genes. [4] . For instance, it is known that S. rimosus carries several tetracycline-resistant determinants, such as otrA, otrB, and otrC (McMurry and Levy, 1998) [32] . Antibiotic-modifying enzymes that are known to exist today are thought to have their origins in the original escape of these naturally occurring ARGs. A study conducted on soil samples collected between 1940 and 2008 revealed a significant increase in the frequency of particular ARGs that confer resistance to erythromycins, tetracyclines, glycopeptides and β-lactams. One such ARG, tetracycline, was roughly 15 times greater in number in 2008 than they are in 1970s (Knapp et al., 2010) [24] . , when donor plasmid carrying transposons co-integrate with recipient plasmid then these transposons can transfer from one plasmid to another plasmids. Integrons are large mobile DNA molecules packed with multiple gene cassettes each consisting of R-genes attached to a small recognition site were first discovered by Stokes and Hall in conjugative plasmids, Vibrio cholera in 1989. The complete element consists of two conserved regions separated by a segment of variable length and sequence which includes inserted antibiotic resistance genes (Stokes and Hull, 1989) [57] . Numerous plasmids contain Tn5393. It was first identified on E. amylovora's large conjugative plasmid pEa34 (34 kb) (Chiou and Jones, 1993) [8] . Thus, this conjugative plasmid may facilitate the HGT-mediated dissemination of genes resistance to streptomycin among E. amylovora or other bacteria, whether pathogenic or non pathogenic. Additionally, Tn5393 was discovered on the E. amylovora plasmid pEa29, where it can insert in multiple places. Unlike pEa34, this 29-kb plasmid cannot be selftransferred to other strains and is unrelated to pEa34. Since pEa29 in E. amylovora is extremely stable, the integration of Tn5393 implies that the resistance has been steadily established in E. amylovora populations. Tn5393a, which lacks Tn5393's IS1133, was found in a number of strains of Pseudomonas syringae and P. marginalis (Han et al., 2004). Additionally, it was found on the conjugative plasmid pEU30 in isolates of E. amylovora (Förster et al., 2015) [15] .

Mechanisms of antibiotic resistance

Antibiotic modification or degradation

Antibiotic modification or degradation is a mechanism of antibiotic resistance in which bacteria possess enzymes or other mechanisms that can chemically modify or break down antibiotics, rendering them ineffective. This mechanism is not limited to plant pathogenic bacteria but can also be found in various types of pathogenic bacteria (Mann et al., 2021). For instance, degradation of streptomycin by the bacterium E. amylovora, which causes fire blight in various fruit trees, including apple and pear trees. E. amylovora has developed resistance to streptomycin by producing an enzyme called streptomycin phosphotransferase (StrA). This enzyme phosphorylates (adds a phosphate group) to streptomycin, which changes the antibiotic's chemical structure. The modified streptomycin is no longer effective at inhibiting bacterial growth, allowing E. amylovora to continue its pathogenic activity (Forster et al., 2015). Gene aadA1 and aadA2 encode enzyme aminoglycoside adenylyltransferases that helps in inactivation of streptomycin that helps in development of streptomycin resistance against X. oryzae pv. oryzae (Xu et al., 2013). strA-strB genes encode phosphostranferases that alter streptomycin into a nontoxic form which provides streptomycin resistance in E. amylovora (Forster et al., 2015).

Antibiotics sequestering

Antibiotic sequestration is a mechanism of antibiotic resistance in which bacteria are capable of trapping or sequestering antibiotics, preventing them from reaching their intended target sites and exerting their antibacterial effects. This mechanism can help plant pathogenic bacteria evade the harmful effects of antibiotics, enabling them to continue causing infections. According to Rudolf et al. (2015), the main antibiotic resistance mechanism is the sequestration of either the metal-free or metal-bound antibiotic by binding proteins ZbmA in Streptomyces flavoviridis.

Target Modification

Target modification is a mechanism of antibiotic resistance in which bacteria alter the target molecules or sites that antibiotics normally interact with, rendering the antibiotics ineffective. In plant pathogenic bacteria, this mechanism can enable them to continue causing infections without the antibiotics inhibiting their growth. An example of target modification in plant pathogenic bacteria is the modification of the ribosomal target site in response to streptomycin. In the case of P. syringae pv. actinidiae which causes bacterial canker of kiwi fruit, the bacteria modify a specific region on their ribosomes, called the S12 protein. This modified S12 protein no longer effectively binds to streptomycin. As a result, the antibiotic is unable to disrupt protein synthesis within the bacterial cell, rendering streptomycin antibiotic less effective or completely ineffective (Cameron and Sarojini, 2014). Streptomycin binds to protein S12, encoded by the rpsL gene of the 30S ribosomal subunit and inhibit protein synthesis. A change in nucleotides at codon 43 of the rpsL gene from AAA, which encodes lysine in streptomycin-sensitive E. amylovora strains, to AGA (arginine), AAT/C (asparagine), or ACA (threonine) conferred a resistance phenotype to the antibiotic observed that gyrA encoded the DNA gyrase subunit A which is target site for oxolinic acid mutation at GyrA helps to develop resistance against oxolinic acid in Burkholderia glumae.

Target Protection

Target protection is a mechanism of antibiotic resistance in which bacteria produce proteins or molecules that shield the target sites of antibiotics, preventing the antibiotics from binding and exerting their inhibitory effects. Tetracycline antibiotics work by binding to the ribosomes of bacteria, disrupting protein synthesis. In response to tetracycline exposure, certain plant pathogenic bacteria, such as Agrobacterium tumefaciens and Agrobacterium vitis, produce Tet proteins, including TetA and TetB, which are membrane transport proteins. These Tet proteins actively pump tetracycline out of the bacterial cells, reducing the intracellular concentration of the antibiotic. By expelling tetracycline from the cell, the Tet proteins protect the ribosomal target sites from the antibiotic. As a result, tetracycline is less effective at inhibiting protein synthesis in these bacteria, allowing them to continue growing and causing infections in plant tissues. Eliminating the antibiotic from the target site offers an additional line of defence against infection. DrrC in S. peucetius removed intercalated daunorubicin/doxorubicin from DNA, enabling normal transcription and replication.

Target Bypass

Target bypass is a mechanism of antibiotic resistance in which bacteria evolve alternative biochemical pathways or use alternative target molecules that circumvent the specific targets of antibiotics. This allows them to continue their growth and metabolic processes despite the presence of the antibiotics. While this resistance mechanism is more commonly associated with pathogenic bacteria in clinical settings, it can also occur in plant pathogenic bacteria. An example of target bypass in plant pathogenic bacteria involves the resistance of Xanthomonas citri subsp. citri to copper-based antibiotics. However, some strains of X. citri subsp. citri have developed resistance to copper antibiotics through target bypass. In this resistance mechanism, the bacteria utilize alternative copper-independent pathways for essential cellular processes, effectively bypassing the need for copper-dependent targets. This adaptation allows the bacteria to continue growing and causing disease in citrus trees, despite the presence of copper-based antibiotics. The production of an extra B subunit of DNA gyrase to confer resistance against novobiocin, an alternative resistant RNA polymerase to confer resistance against rifamycin, or an alternative fatty acid synthase to confer ability to withstand platensimycin.

Antibiotic Efflux

Antibiotic efflux is a mechanism of antibiotic resistance in which bacteria actively pump antibiotics out of their cells, reducing the intracellular concentration of the drug. This mechanism is common in both clinical and plant pathogenic bacteria. According to Herbert et al. (2022) [19] , TetC encodes ABC (ATP binding cascade) transporter that remove excessive amount of oxytetracycline and streptocyclin from antibiotic efflux Xanthomonas arboricola pv. pruni cytosol to ouside of the cell and reduce its concentration in cytosol that helps to develop resistance against these antibiotics. Antibiotic efflux is a significant challenge in the management of plant diseases, as it allows bacteria to expel antibiotics and maintain their virulence. It underscores the need for innovative strategies for plant disease control that are less susceptible to bacterial resistance mechanisms, such as efflux pumps. ABC (ATP binding cascade) transporters helps in efflux of oxytetracycline with the help of otrC and DrrAB efflux system in antibiotic producer bacteria as S. rimosus and S. peucetius, respectively (Yu et al., 2012; Mak et al., 2014) [28] . [5] 23S rRNA methylation (MLS) Clr, PikR1, PikR2 Chromosome S. caelestis (clr); S. venezuelae (pikR1, pikR2)

Calcutt and Cundliffe (1990) [6] ; Almutairi et al. (2015) [1] 16S rRNA methylation (Amynoglycosides) PCT, Sgm methylase Chromosome S. pactum (pct) M. zionesis (sgm)

Ballesta and Cundliffe (1991) [3] ; Kojic et al. (1992) [25] Antibiotic target bypass DNA gyrase subunit B (novobiocin) Chromosome S. sphaeroides (gyrBR) Schmutz et al. (2003) [53] Antibiotic target protection Antibiotic removal DrrC (Dox) OtrA (oxytetracycline)

Chromosome S. peucetius (drrC) S. rimosus (otrA) Doyle et al. (1991) [14] ; Mak et al. (2014) [28] ; Prija and Prasad (2017) [68] Streptomycin E. amylovora California, USA Chromosomal mutation, rpsL mutation, strAB on plasmid RSF1010, Tn5393a 32

Schroth et al. (1979) [54] Chiou and Jones, (1995) [8] ; Palmer et al. (1997) [39] [34] P. syringae pv. syringae Oklahoma, USA Tn5393a Sundin and Bender (1993) [58] Xanthomonas axonopodis pv. vesicatoria Argentina Tn5393b Sundin and Bender (1995) [59] Xanthomonas citri subsp. citri Korea strBc Hyun et al. (2012) [22] Collaboration between researchers, agricultural practitioners, and policymakers is essential to develop and implement effective strategies for managing antibiotic resistance in plant pathogenic bacteria. Continued surveillance and research efforts are crucial for staying ahead of evolving resistance patterns and identifying new potential targets for intervention. Ultimately, addressing antibiotic resistance in plant pathogenic bacteria is not only vital for safeguarding crop health and yield but also for preserving the long-term sustainability of agriculture. A holistic and proactive approach that combines scientific innovation, responsible antibiotic use, and sustainable agricultural practices will be key to mitigating the impact of antibiotic resistance on global food security.

Future Aspects • Genomic Studies and Target Identification:

Continued advancements in genomics and bioinformatics will play a pivotal role in identifying specific genetic determinants associated with antibiotic resistance in plant pathogenic bacteria. Targeting these specific genes or pathways could lead to the development of novel and more effective antibacterial agents.

• Antibiotic Alternatives: Research into alternative methods for controlling bacterial infections in plants without relying on antibiotics will likely gain momentum. This could include the development of biopesticides, plant immune system enhancers, or bacteriophage-based therapies. • By embracing these future aspects, the scientific community, agricultural practitioners, and policymakers can work together to develop sustainable and effective solutions to the growing challenge of antibiotic resistance in plant pathogenic bacteria. This multidisciplinary approach is crucial for ensuring the long-term health and productivity of global agriculture.

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