Sexually transmitted infections (STIs) are a global public health challenge, severely affecting the quality of life and giving rise to substantial morbidity and mortality. STIs have a negative influence on the reproductive and child health, leading to complications such as infertility and pregnancy-related issues [1]. Most STIs facilitate the transmission of HIV, amplifying their impact on both national economies and the individual well-being [1]. Prioritizing STIs prevention and control is a paramount public health concern [2]. Curable STIs alone result in the loss of over eleven million disability-adjusted life years annually, and it is estimated that more than a million STIs are contracted daily worldwide, with infections including chlamydia, gonorrhea, syphilis, trichomoniasis, herpes simplex virus (HSV), human papillomavirus (HPV), and HIV falling under the broad category of these infections [2,3,4,5]. More than 1 million STIs every day are acquired. As reported by the WHO, in 2020, 374 million new infections with one of four STIs occurred. Chlamydia cases totaled 129 million, gonorrhea totaled 82 million, syphilis totaled 7.1 million and trichomoniasis totaled 156 million. Over 490 million people were believed to have genital herpes in 2016, and 300 million women were believed to have HPV infection.

Gonorrhea is the second most common bacterial STI inflicting considerable morbidity and substantial economic costs on a global scale [6]. Gonococci success as human pathogens is the result of several combined factors. The plethora of bacterial virulence factors allow efficient colonization of both male and female mucosae. The chameleon-like ability determined by the high-frequency antigenic and phase variation of core surface structures causes clonal variability. The ability to subvert and hide from the immune system by directly suppressing and interacting with immunological effectors and regulators allows re-infections. N. gonorrhoeae infections encompass a multi-step strategic process: pathogen highly efficient transmission; mucosal localized adherence; local proliferation and invasion; local inflammatory response; external or systemic dissemination. Presently, there is no effective vaccine directly targeting Neisseria gonorrhoeae available in clinical practice, although data support the possible use of multicomponent meningococcal serogroup B (4CMenB) vaccine to provide some cross-protection and also prevent Neisseria gonorrhoeae cases [2,3,4,5,6,7]. With the emergence of multidrug-resistant (MDR) strains and the lack of new antibiotics, the World Health Organization (WHO) has recognized the health sector’s response to the epidemic of STIs as a critical component in achieving universal health coverage [8]. This objective is delineated in the 2030 Agenda for Sustainable Development, encapsulating the Sustainable Development Goals (SDGs) [9,10]. However, the sustainable control of infections may not be reached with the current interventions, necessitating also innovative solutions.

In 2016, eighty-seven million new cases of Neisseria gonorrhoeae were estimated worldwide, with varying prevalence and incidence across the world and higher risk among younger individuals [11]. The highest rates were observed in low and middle-income countries, as transmission is often linked to the socio-economic status. Notably, gonorrhea prevalence among women was high in the WHO African region, the Americas, and the Western Pacific, while lower prevalence was observed in Europe. However, an increase in cases in Western countries is currently observed, which can be attributed to improved diagnostics and evolving sexual networks [11,12]. Moreover, in the African region, Neisseria gonorrhoeae during pregnancy poses a substantial burden, reaching a prevalence comparable to that of malaria [13]. Focusing on Europe, an increasing trend in cases is observed among all key populations with the most significant rise observed among men who have sex with men (MSM) [14,15,16,17]. Moreover, international travels play a key role in the spread of multi-resistant STIs, and therefore, improved surveillance in international travelers is needed. However, reported data are likely underestimated due to underreporting and the presence of asymptomatic cases. The bacterium’s emergence as an MDR pathogen has led to its inclusion in the “WHO Priority Pathogens List for Research and Development of New Antibiotics” [10]. Remarkably, N. gonorrhoeae is the only STI in the list; the second level of priority [10]. Indeed, the “World Health Organization Global Gonococcal Antimicrobial Surveillance Program,” known as the WHO GASP, is designed to monitor the emergence of MDR and extensively drug-resistant (XDR) strains [18]. The WHO recommends discontinuing first-line treatments when failures or not susceptible isolates are above 5%. Data from 2015 to 2016 show that 100% of countries reported ciprofloxacin resistance, 80% reported resistance to azithromycin, 45% reported resistance to cefixime and 24% reported resistance to ceftriaxone [18]. Ceftriaxone resistance is rare in the Euro-GASP countries when compared to other regions, whilst azithromycin resistance is highly prevalent also in the European region, although travel-related spread of MDR lineages is observed [18]. Moreover, the WHO established the Global Antimicrobial Resistance Surveillance System (GLASS) in 2019 [19].

Gonorrhea infections involve the genital, rectal, and pharyngeal regions and may be either asymptomatic or symptomatic. Most acute lower tract infections in females, around 80–90% of cases, are asymptomatic, while lower tract infections in men are symptomatic in approximately 45% of cases. Extra-genital gonococcal infections are often asymptomatic among both men and women [3,11]. Complications can arise from both symptomatic and asymptomatic infections. The most common adverse outcomes are related to sexual and reproductive health and include upper genital tract dissemination, leading to pelvic inflammatory disease (PID), Fitz Hugh Curtis syndrome, tubal-ovarian abscess, epididymo-orchitis, bartholinitis, penile lymphangitis, and edema [11,20]. Genital tract scarring and adverse pregnancy outcomes also contribute to gonorrhea morbidity [11,20,21,22,23]. Rarely, gonorrhea may also present as disseminated gonococcal infection (DGI), which include gonococcemia, gonococcal arthritis, tenosynovitis, osteomyelitis, endocarditis, and meningitis [24,25]. Lastly, gonorrhea increases the risk of HIV acquisition, transmission, with often presence of co-infection with other STIs [26,27].

5. Novel Antibiotics Showing Inferiority to First-Line Treatment Options

5.1. Solithromycin

5.2. Delafloxacin

6. New Antibiotics Candidates

6.1. Zoliflodacin

6.2. Gepotidacin